Molecular mechanisms regulating the hyaluronan binding activity of the adhesion protein CD44.

In the present study, we describe the isolation and characterization of a cDNA clone designated B6F1.3, that appears to 'activate' the hyaluronan-binding capacity of CD44 upon transfection into the murine fibroblastoid cell line MOP8. Sequence analysis indicates that the putative regulatory molecule encoded by this clone is identical to the murine interleukin-2 receptor gamma chain (mIL-2R gamma), a recently described type 1 transmembrane protein that constitutes an integral component of the cell surface receptors that bind a number of cytokines including IL-2, IL-4, IL-7, IL-9, IL-15 and perhaps also IL-13. Mutations in this molecule have been shown to be responsible for X-linked severe combined immunodeficiency (XSCID) in humans. With the exception of bone marrow, the mIL-2R gamma chain was found to be expressed at high levels on all hemopoietic cell lines and tissue types examined. Non-hemopoietic tissues are generally negative. FACS analysis and Western blot analysis indicated respectively that B6F1.3 does not mediate its effects by upregulating the expression of CD44 or by altering the alternative splicing of the molecule. Removal of the cytoplasmic tail of the mIL-2R gamma chain, including a Src homology region 2 (SH2) subdomain, abolished its ability to enhance CD44-mediated binding to hyaluronan suggesting the involvement of signal transduction events triggered via the cytoplasmic domain in the 'activation' process. Determining whether activating molecules such as B6F1.3 are co-expressed within tumor cells may help improve the potential value of CD44 as a diagnostic marker of metastatic disease.

Gene therapeutic approach to primary and metastatic brain tumors: I. CD44 variant pre-RNA alternative splicing as a CEPT control element.

Our laboratory and others have shown alternative splicing of up to ten exons at a discrete extracellular site to be primarily responsible for the generation of CD44 variant (CD44v) isoforms. Based on clear differences in the expression of these CD44v isoforms between normal and malignant tissues, we believe that elucidation of the mechanisms underlying the regulation of CD44 alternative splicing may provide a new gene therapeutic targeting approach based on CD44 pre-mRNA processing in vivo. This strategy incorporates utilization of CD44 alternative splicing control elements into a chimeric enzyme/prodrug therapy (CEPT), a novel modification of the virus-directed enzyme/prodrug therapy (VDEPT) approach for the treatment of brain metastases from tumors of systemic origin. As initial steps towards the development of a gene therapeutic approach based on targeting tumor cell expression of specific CD44v alternatively spliced isoforms, we have: (1) developed a novel in vivo assay system that allows the rapid analyses of potentially therapeutic CD44 alternative splicing minigene constructs; and (2) cloned the E. coli cytosine deaminase (CD) gene and fused its enzymatically active domain to alternatively spliced CD44 exons (CD44/CD). Deamination of cytosine by this CD44/CD chimeric fusion protein is demonstrated in E. coli cell lysates to be equal to that of wild type cytosine deaminase.

Adhesive interactions between alternatively spliced CD44 isoforms.

Alternative splicing of a series of 10 contiguous exons present within the CD44 gene can generate a large number of differentially expressed CD44 isoforms that contain additional peptide sequences of varying length inserted into a single site within the extracellular domain of the molecule proximal to the membrane spanning domain. Although distinct functions have been ascribed to certain of these isoforms, the effect of particular inserted domains on the ligand-binding specificity of the CD44 molecule remains unclear. In the present study, we demonstrate that while CD44H, the major CD44 isoform expressed on resting hemopoietic cells, and CD44R1, an alternatively spliced isoform present on transformed epithelial cells and certain activated and/or malignant hemopoietic cell types, can both bind avidly to hyaluronan, only CD44R1 can promote homotypic cellular aggregation when expressed in the CD44-negative murine lymphoma cell line TIL1. Experiments in which TIL1 cells transduced with different CD44 isoforms were tested for their ability to adhere to one another or to COS7 cells transfected with CD44R1, indicated that CD44R1 can recognize and bind a common determinant present on both CD44H and CD44R1. Monoclonal antibody blocking studies suggest further, that the determinant recognized by CD44R1 is located in a region of the CD44 molecule distinct from that involved in hyaluronan binding.

A Pain Rating Scale and a Pain Behavior Checklist for clinical use: development, norms, and the consistency score.

A Pain Rating Scale [PRS] and a Pain Behavior Checklist [PBC] were developed for use during a clinical pain interview. Norms were based on 395 chronic pain patients referred for pain management. The PRS obtained ratings of present pain, and worst and least pain during the previous 30 days. The PBC recorded 16 pain behaviors during the 45- to 60-min interview. Normative data were given for seven measures: (1) worst pain rating, past month; (2) least pain rating, past month; (3) present pain rating; (4) difference between worst and least pain ratings; (5) pain behavior score; (6) total pain score (based on Nos. 1, 2, 3, and 5), and (7) consistency score. The consistency score reflects the agreement (or discrepancy) between the pain behavior and present pain ratings. A moderate overall relationship was found between pain behavior and present pain ratings (r = 0.46, p < 0.001). The frequency of good agreement between pain behavior and present pain ratings was unaffected by sex, race, age, pain site, type of injury, duration of pain, legal representation, and evaluating psychologist; but it varied markedly with conscious symptom magnification. Patients seen as consciously exaggerating pain (n = 127) gave higher pain ratings (all p values < 0.001); and had frequent (64.6%) discrepancies between their pain report and pain behavior compared to others (14.2%). The report of present pain was unrelated to pain behavior for conscious exaggerators (r = 0.04, NS); in contrast there was a moderately high relationship for other patients (r = 0.68, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

As-needed medication use in asthma usage patterns and patient characteristics.

Daily inhaled bronchodilator medication usage was recorded using an electronic device and airway obstruction by daily peak flow measurement. The demographic, clinical, and psychological characteristics of the subjects were noted. Subjects were allocated to as-needed (prn) medication usage groups according to the mean number of inhaler activations on days with zero, moderate, and severe airway obstruction. Segregation into arbitrary and nonarbitrary use, and into overuse, appropriate use, and underuse resulted in six usage groups. Appropriate use was observed in only 10 of 39 subjects. The major psychological variable to differ among groups was the MMPI variable Pt, representing general anxiety. Arbitrary users had a significantly higher mean score than nonarbitrary users. The variable Specific Internal Awareness, representing a perceived difficulty in recognizing the premonitory symptoms of an asthma attack, also differed among the usage groups, with arbitrary users having the lowest scores. These findings raise the possibility that reliance on an objective measurement of airway obstruction rather than on subjective symptomatology might enhance compliance with prn medication in some patients.

Multidimensional analysis of peak pain symptoms and experiences.

Peak pain symptoms and experiences were explored within a group of 243 intractable pain patients seen consecutively at a pain clinic. Using a 5-point scale, patients rated the frequency with which 99 symptom adjectives occurred when their pain was at its worst. Key cluster analysis identified 11 reliable, conceptually clear symptom clusters: Four affective symptom categories, Angry Depression, Diminished Drive, Intropunitive Depression and Anxiety, describing emotional states concomitant with peak pain; two somatic symptom categories, Ecto-Pain and Endo-Pain, describing surface and deep bodily pain, respectively; and five additional symptom categories including Cognitive Dysfunction, Sleep Disturbance, Fatigue, Withdrawal and Disequilibrium. Among the affective symptom clusters, symptoms of Angry Depression were reported to occur frequently by 32% of the patients while only 11% reported the frequent occurrence of Intropunitive Depression. For the somatic symptom clusters, 25 and 52% reported the frequent occurrence of Ecto-Pain and Endo-Pain, respectively. Pain reports measured by Ecto-Pain and Endo-Pain were nearly independent of all other symptom categories. The results suggest that the experiential context of pain differs widely among intractable pain patients. The study derived a Pain Symptom Checklist to measure each symptom cluster as one way to identify coping styles among chronic pain patients.

Subscales to the Taylor Manifest Anxiety Scale in three chronically ill populations.

In a sample of 150 people drawn from a population of asthma, tuberculosis, and chronic pain patients, a key cluster analysis revealed five different clusters of items in the Taylor Manifest Anxiety Scale: Restlessness, Embarrassment, Sensitivity, Physiological Anxiety, and Self-Confidence. These clusters are consistent and four of them appear moderately related, whereas Embarrassment is fairly independent of the others.

Multidimensional analysis of the symptoms of chronic bronchitis and emphysema.

Subjective symptoms and experiences were explored within a group of 146 severe, chronic bronchitis and emphysema patients. Eighty-nine symptoms and experiences, derived from initial interviews with 29 patients, were rated according to the frequency of occurrence during breathing difficulties. Key cluster analyses were used to derive a Bronchitis-Emphysema Symptom Checklist (BESC) measuring 11 symptom categories: Helplessness-Hopelessness, Decathexis, Fatigue, Poor Memory, Peripheral-Sensory Complaints, Dyspnea, Congestion, Sleep Difficulties, Irritability, Anxiety, and Alienation. The BESC symptom categories are highly reliable and the relationships among categories are stable across two subgroups of patients. The BESC provides one way to describe how patients cope with and experience chronic bronchitis and emphysema.

Symptoms and experiences in chronic bronchitis and emphysema.

A heterogeneous group of 146 patients with chronic bronchitis and emphysema were asked to rate the frequency with which 89 symptoms and experiences occurred during their breathing difficulties. Normative values and the reported frequency of occurrence for the 11 symptom categories are presented. As expected, symptoms of dyspnea were the most frequently reported during breathing difficulties. In decreasing order, symptoms of dyspnea were followed by symptoms of fatigue, sleep disturbance, congestion, irritability, anxiety, decathexis, helplessness-hopelessness, poor memory, alienation. Separation of the patients into subgroups revealed that women reported more anxiety and helplessness-hopelessness than men. Younger patients reported more irritability and anxiety than older patients. Patients with mixed disease reported more dyspnea than those with chronic bronchitis or emphysema, although patients with emphysema reported more loss of interest in life than patients with chronic bronchitis. Self-ratings of functional incapacitation were clearly related to the symptom reports. Relationships among the symptom categories were discussed, as was the potential usefulness of symptom patterns in exploring coping styles in respiratory disease.

Characteristics of depression of chronically ill medical patients. An elaboration of personality styles.

In an earlier study, 13 distinct patterns of depression were found among 132 asthma, tuberculosis, and pain patients. The subscales of scale 2 of the Minnesota multiphasic personality inventory (MMPI) which were developed at the Massachusetts Mental Health Center were the basis for the classification via o-type cluster analysis. The present work projected these patterns to the standard three validity and ten clinical scales of the MMPI. In addition, Dirk's panic-fear and Kleiger's alexithymia scales were scored. It was demonstrated that these 13 patterns of depression had important personality correlates associated with them. A useful point of view to take in medical care of the chronically ill is also offered.

The influence of corticosteroids and theophylline on cerebral function. A review.

Evidence indicating that corticosteroid therapy may adversely affect attention and memory in asthmatic subjects is reviewed. The potential impact of corticosteroid dosage levels (high versus low) and treatment regimens (daily versus alternate day) on attention and memory is discussed. Findings indicate that the suppression of ACTH by corticosteroids may have different effects on attention and memory as a function of the sex of the asthmatic patient. The need to establish what the effects of theophylline-induced reductions of cerebral blood flow and cerebral oxygen tension are on higher cognitive processes are outlined. The importance of establishing whether or not medications commonly used for the treatment of asthma create deficits of memory or attention that interfere with medical compliance is emphasized.

Patient mislabeling of symptoms: implications for patient-physician communication and medical outcome.

Mislabeling of symptoms was studied in a group of 587 chronic asthmatic patients. Results indicated a wide variation in both the frequency and type of mislabeling, with over 26 per cent of the patients mislabeling one or more nonairways obstruction symptom clusters as being an asthma attack. Several demographic and personality factors were found to correlate with mislabeling. Finally, mislabeling was associated with medical outcome, with mislabelers being 40 per cent more likely than nonmislabelers to be rehospitalized for their asthma within six months of discharge.

The battery of asthma illness behavior, I: independence from age of asthma onset.

The Battery of Asthma Illness Behavior was developed to assess the potential for psychomaintenance in chronic bronchial asthma. The present study demonstrates that the BAIB's success in predicting the perpetuation, exacerbation, and maintenance of asthma cannot be attributed to its merely reflecting one objective parameter of illness, i.e., age of asthma onset.

The battery of asthma illness behavior, II: independence from airways hyperreactivity.

Bronchial asthma is an illness particularly susceptible to psychological and behavioral exacerbation and perpetuation. The Battery of Asthma Illness Behavior has demonstrated a remarkable ability to identify such psychomaintenance potentials in chronic asthmatic patients. The present study advances previous research by showing that BAIB scores are independent of degree of airways hyperreactivity. This finding strengthens the assertion that the BAIB assesses psychomaintenance potentials independent from the objective medical parameters of the illness.

The battery of asthma illness behavior, III: independence from longitudinal pulmonary functions.

Previous research has demonstrated that the Battery of Asthma Illness Behavior is related to a wide variety of medical outcome variables in bronchial asthma. It has been maintained that BAIB scores reflect the degree to which psychological and behavioral factors can adversely affect medical management and prognosis. The present study advances previous research by investigating the relationship between BAIB scores and average longitudinal spirometry.

Improving patient recall and comprehension of the treatment regimen.

The failure of patients to comprehend medical advice or to recall accurately the instructions their physicians give them may destroy the effectiveness of even the most scientifically sound treatment regimen. The proper use of practical and simple communication techniques may greatly assist the physician in educating the patient. Knowledge of the current status of research on the recall of medical information will assist the practitioner in communicating so that patients can improve their retention of medical instructions and advice.

Death in asthma: a psychosomatic autopsy.

In most, if not all, chronic illnesses, the patient is a participant in medical management. Attitudes and behaviors during treatment can influence medical outcome in important ways that are becoming increasingly understood. This case history illustrates how a personal style may have contributed to the worst possible outcome, death, in an illness that is usually not fatal. There is a need to unravel the complex interplay between the psychological and medical factors contributing to such extremes in medical treatment failure in order to permit timely and appropriate intervention.