Regulatable gene expression systems for gene therapy applications: progress and future challenges.

Gene therapy aims to revert diseased phenotypes by the use of both viral and nonviral gene delivery systems. Substantial progress has been made in making gene transfer vehicles more efficient, less toxic, and nonimmunogenic and in allowing long-term transgene expression. One of the key issues in successfully implementing gene therapies in the clinical setting is to be able to regulate gene expression very tightly and consistently as and when it is needed. The regulation ought to be achievable using a compound that should be nontoxic, be able to penetrate into the desired target tissue or organ, and have a half-life of a few hours (as opposed to minutes or days) so that when withdrawn or added (depending on the regulatable system used) gene expression can be turned "on" or "off" quickly and effectively. Also, the genetic switches employed should ideally be nonimmunogenic in the host. The ability to switch transgenes on and off would be of paramount importance not only when the therapy is no longer needed, but also in the case of the development of adverse side effects to the therapy. Many regulatable systems are currently under development and some, i.e., the tetracycline-dependent transcriptional switch, have been used successfully for in vivo preclinical applications. Despite this, there are no examples of switches that have been employed in a human clinical trial. In this review, we aim to highlight the main regulatable systems currently under development, the gene transfer systems employed for their expression, and also the preclinical models in which they have been used successfully. We also discuss the substantial challenges that still remain before these regulatable switches can be employed in the clinical setting.

X11alpha modulates secretory and endocytic trafficking and metabolism of amyloid precursor protein: mutational analysis of the YENPTY sequence.

The neuronal adaptor X11alpha interacts with the conserved -GYENPTY- sequence in the C-terminus of amyloid precursor protein (APP) or its Swedish mutation (APPswe) to inhibit Abeta40 and Abeta42 secretion. We hypothesized that the -YENP- motif essential for APP endocytosis is also essential for X11alpha-mediated effects on APP trafficking and metabolism, and that X11alpha modulates APP metabolism in both secretory and endocytic pathways. X11alpha failed to interact with the endocytic-defective APPswe mutants Y738A, N740A, or P741A, and thus did not modulate their trafficking or metabolism. However, endocytic-competent APPswe Y743A had unique trafficking and metabolism including a prolonged half-life and increased secretion of catabolites compared with APPswe. In contrast to endocytic-defective mutants, X11alpha interacted with APPswe Y743A as well as with APPswe. Thus, similar to APPswe, coexpression of X11alpha with APPswe Y743A retarded its maturation, prolonged its half-life, and inhibited APPs, Abeta40, and Abeta42 secretion. Collectively, these data suggest that by direct interaction with the APPswe -YENP- motif in the cytoplasmic tail, X11alpha modulated its trafficking and processing in both secretory and endocytic compartments, and may reduce secretion of Abeta generated in either pathway.

Minnesota Multiphasic Personality Inventory as a predictor of operative results in thoracic outlet syndrome.

Twenty-one women and four men who had been operated upon for thoracic outlet syndrome were evaluated for symptom relief, and the results were blindly correlated with their scores on a Minnesota Multiphasic Personality Inventory (MMPI). Of the 14 patients who had abnormal results on the MMPI, five rated themselves improved, seven unchanged, and two worse as a result of surgery. Of the 11 patients who had a normal MMPI, ten rated themselves improved and one unchanged (P less than .05). Patients were then divided into two groups--those who were improved and those who were not improved by surgery--and mean MMPI scale scores were obtained for each group. There were significant differences for MMPI scales 1 and 3 (P less than .05).

Normative data on the Missouri Children's Picture Series and the Missouri Children's Behavior Checklist with Southern black children.

Normative data are presented for Southern black children on two objective personality inventories for children: the Missouri Children's Picture Series (MCPS), a child picture-sorting task, and the Missouri Children's Behavior Checklist (MBCL), a parent rating scale. The MCPS was administered to 615 black children attending public schools in a low socioeconomic area of the southeast United States. Parents returned the MBCL on 437 of the children. Means and standard deviations on eight MCPS personality scales and six MCBL behavior rating scales are presented for black males and females at ages 5 through 16, and effects of age, sex, and various scale intercorrelations are discussed. Results suggest systematic age and sex differences on the various scales for black children that are quite atypical when compared with the MCPS in other samples. Various empirical questions regarding the validity of these instruments when used with Southern black children are raised.

The selection of paraprofessional telephone counselors using the California Psychological Inventory.

Comparing groups of 36 veteran telephone counselors with 36 matched age and sex control subjects on the CPI revealed substantial differences on a number of scales. Subsequent development of weighted formulae via regression analysis led to very accurate predictions as to which individuals were telephone counselors or controls. Various cutoff scores and their uses are discussed.

Two- and three-point classification of MMPI profiles in which scales 2, 7, and 8 are the highest elevations.

Two-point and three-point methods of classifying MMPI profiles were compared using 174 students who sought psychological treatment at a college student mental health clinic and who generated MMPI profiles with scales 2, 7, and 8 as their highest evaluations, (or obtained two of those three scales as their two highest elevations). Behavioral correlates were determined by comparing each profile type to the remainder of the population by means of the chi2 statistic for males and females. Each two-point code type was compared to the comparable subgroup of its parent three-point code type. Important differences in interpretation were present between two- and three-point classification methods, particularly when sex of subject was considered, suggesting that method of classification and sex of subject are important variables in the accurate interpretation of college student MMPI profiles.

Behavioral correlates of infrequent two-point MMPI code types at a university mental health center.

Presented interpretive correlates for 95 college students who were seeking mental health services and who generated the following infrequently occurring MMPI code types: Spike 2, 2-0/0-2, 2-4/4-2, 2-6/6-2, 3-4/4-3, 3-9/9-3, 4-7/7-4, 6-7/7-6, 7-9/9-7, and Spike O. Descriptors were derived from intake interview and mental status information collected without knowledge of the MMPI profile. Those items that discriminated between each profile type and the remainder of the student mental health population (Chi Square, alpha = .05, .01) are presented as tentative interpretive descriptors that may be helpful in generating hypotheses for use with college student psychiatric outpatients.

Cross validation of the 2-8/8-2 MMPI code type for young adult psychiatric outpatients.

Young adults attending a college student mental health center and obtaining 2 and 8 as their highest scale elevations (and not scale 7 as the third elevation) on the MMPI were compared to other patients at the center on 175 descriptors obtained from intake interviews. Those items which discriminated (chi2, p less than .05) 2-8/8-2 patients from others in the sample are presented in relationship to the descriptors obtained for this code type by other investigators. The statements generated by the Marks and Seeman interpretive system for adults were then reanalyzed by the Chi Square method to demonstrate the differential effect of statistical method upon code type interpretation. Although previously established correlates of 2-8/8-2 profiles were partially validated, a number of different descriptors emerge for males and females in this population. Questions are raised and discussed concerning methodologies for generating interpretive statements for various clinical populations.

A comparison of three survey methods to obtain data for community mental health program planning.

A perennial problem for mental health planners is assessing community needs and existing services. The three most common methods used to obtain this data are the telephone survey, the mail-out questionnaire, and the face-to-face interview. However, there are advantages and disadvantages associated with each approach in terms of sampling, response rates, and economic costs. The present study utilized all three methods to survey the same community population in order to determine the comparability of obtained data and relative efficacy of the methods. A standard 21-item questionnaire was developed to obtain demographic and epidemiological data. This included nine Likert-type items to obtain opionions on a typical question such as "To what extent would you have confidence in recommending the Mental Health Center to members of your immediate family?" In the first method, survey teams made door-to-door interviews to complete 449 questionnaires on a random sample. In the second method, 1,000 questionnaires were mailed to a random sample with returns requested. In the third method, 224 people were randomly selected from the telephone directory and asked to respond to the questionnaire over the phone. Precautions were taken in all methods to ensure confidentiality of responses. All respondents were classified according to a two-factor index based on occupation and education. The data were analyed to determine whether comparable data were obtained through divergent methods. Results are discussed and implications are given for community mental health planners.

Behavioral correlates for within-normal-limit MMPI profiles with and without elevated K in students at a university mental health center.

Young adults who were attending a college student mental health center and who obtained MMPI profiles with clinical scales within normal limits with and without elevated K were compared to all other patients at the center on 175 descriptors obtained from intake interviews. Those items that discriminated (x2, p less than .05) students who obtained these profile types from others are reported as tentative MMPI interpretive correlates for patients in similar settings. Correlates ranged from those indicative of situational difficulties to serious psychopathology, and clear sex differences were present. It is concluded that within-normal-limit profiles do not indicate psychological normality when they occur in such a setting and that useful interpretive information can be identified for these, as well as clinically elevated profile types.

Behavioral correlates for spike-4, spike-9, and 4-9/9-4 MMPI profiles in students at a university mental health center.

Numerous investigators have noted that spike-4, spike-9, and 4-9/9-4 profiles occur with an unusually high frequency in college students. Five hundred and fifty files of college students who requested outpatient psychiatric services were reviewed, and the data from 47 files were extracted in which the student patient had a clinically elevated spike-4, spike-9, or 4-9/9-4 profile. Numerous significant psychopathological behavioral correlates were found for each profile type, which supports the contention that these profile types are reflective of significant psychopathology and are not examples of benign deviations of a particular sample from the original normative group.

Roles and expectations for mental health professionals in law enforcement agencies.

To assess consumer needs for and attitudes toward mental health services within law enforcement agencies, a questionnaire composed of a comprehensive list of mental health services potentially available to police departments was administered to populations of police officers and mental health workers. Respondents rated the services according to perceived utility of the service for law enforcement needs. Generally, police officers seemed receptive to several kinds of mental health service, although they were less enthusiastic about the value of the services than professionals. The implication of these data for the community mental health worker are discussed in terms of establishing and maintaining effective, mutually satisfying relationships with law enforcement agencies.

An evaluation of the effectiveness of a telephone counseling center.

Three-thousand questionnaires were distributed to students on campus to identify a sample of actual telephone counseling center users and their ratings of the effectiveness of the help received and of the counselor. Ratings of help received and impact of counseling on life as it is today were considered for sex of caller and counselor across type of problem. A sample of 66 actual callers was identified who had used the service for personal problems at least once. Of male callers, 67% reported that telephone counseling helped at least somewhat, while 80% of female callers reported favorable results of telephone counseling. Female callers who talked with male counselors reported a significantly greater impact on their life than did the callers in any other caller/counselor sex interaction. Only one average rating of counseling effectiveness by problem type fell below the neutral rating. Results are presented as evidence for the effectiveness of paraprofessional counselors.