Search PubMed⌕ Search

Biomedical subjects

D F Klein

Publications and source records attributed to D F Klein.

At least 19 recordsLinked to original sources
PubMed2001

Eosinophils are a major source of nitric oxide-derived oxidants in severe asthma: characterization of pathways available to eosinophils for generating reactive nitrogen species.

Eosinophil recruitment and enhanced production of NO are characteristic features of asthma. However, neither the ability of eosinophils to generate NO-derived oxidants nor their role in nitration of targets during asthma is established. Using gas chromatography-mass spectrometry we demonstrate a 10-fold increase in 3-nitrotyrosine (NO(2)Y) content, a global marker of protein modification by reactive nitrogen species, in proteins recovered from bronchoalveolar lavage of severe asthmatic patients (480 +/- 198 micromol/mol tyrosine; n = 11) compared with nonasthmatic subjects (52.5 +/- 40.7 micromol/mol tyrosine; n = 12). Parallel gas chromatography-mass spectrometry analyses of bronchoalveolar lavage proteins for 3-bromotyrosine (BrY) and 3-chlorotyrosine (ClY), selective markers of eosinophil peroxidase (EPO)- and myeloperoxidase-catalyzed oxidation, respectively, demonstrated a dramatic preferential formation of BrY in asthmatic (1093 +/- 457 micromol BrY/mol tyrosine; 161 +/- 88 micromol ClY/mol tyrosine; n = 11 each) compared with nonasthmatic subjects (13 +/- 14.5 micromol BrY/mol tyrosine; 65 +/- 69 micromol ClY/mol tyrosine; n = 12 each). Bronchial tissue from individuals who died of asthma demonstrated the most intense anti-NO(2)Y immunostaining in epitopes that colocalized with eosinophils. Although eosinophils from normal subjects failed to generate detectable levels of NO, NO(2-), NO(3-), or NO(2)Y, tyrosine nitration was promoted by eosinophils activated either in the presence of physiological levels of NO(2-) or an exogenous NO source. At low, but not high (e.g., >2 microM/min), rates of NO flux, EPO inhibitors and catalase markedly attenuated aromatic nitration. These results identify eosinophils as a major source of oxidants during asthma. They also demonstrate that eosinophils use distinct mechanisms for generating NO-derived oxidants and identify EPO as an enzymatic source of nitrating intermediates in eosinophils.

Eosinophil Peroxidase↗
PubMed2001

Acute panic inventory symptoms during CO(2) inhalation and room-air hyperventilation among panic disorder patients and normal controls.

There is scant literature on anxiety symptoms induced during respiratory challenges developed to induce panic symptoms and attacks. Here we report on the prevalence of Acute Panic Inventory (API) symptoms during three consecutive respiratory challenges to patients with panic disorder (PD) and normal controls (NC). The challenges performed using a closed canopy system included voluntary room air hyperventilation (RAH), inhalation of 5% CO(2), and 7% CO(2)-enriched air. The PD patients were 41 men and 53 women whose mean age was 33.4 (SD = 8.55). The normal comparison group consisted of 35 men and 27 women with a mean age of 31.3 (SD = 9.21). The diagnosis of panic disorder was made using the Structured Clinical Interview for DSM-III-R. All potential normal controls underwent structured clinical interview using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version Modified for the Study of Anxiety Disorders (SADS-LA), and must have been free of a lifetime history of anxiety disorders, affective disorders, substance use disorders, and schizophrenia. All participants also had a complete medical evaluation and were in good health. The experiment consisted of seven experimental epochs: three baseline/recovery periods each followed by a respiratory challenge, and then a final recovery epoch. The API was administered at the end of each epoch. Clinical staff trained and experienced in rating panic attacks rated participants' response during each challenge as panic or no panic. Three groups were defined for analysis: PD patients who panicked, PD patients who did not panic, and NC who did not panic. Staff ratings indicated that the 7% CO(2) challenge was the most panicogenic, followed by the 5% CO(2), and the RAH challenges. Conventional statistics (analysis of variance and partial correlations) indicated that many baseline symptoms as well as symptom increments differed across groups, and were associated with the outcome of panic/no panic during each challenge. However, logistic regression analysis indicated that only a few symptoms independently predicted the panic/no panic outcome because many symptoms were redundant. The symptom cluster of fear in general, dizziness, difficulties with concentrating, and doing one's job predicted panic to RAH. The cluster of fear in general, confusion, dyspnea, and twitching/trembling predicted the response to 5% CO(2). Finally, fear in general, confusion, twitching/ trembling and dizziness predicted the response to 7% CO(2). While univariate analyses indicated that many symptoms distinguished between panic and no panic outcome, logistic regression revealed that group differences were subsumed under a few prominent symptoms, namely, fear in general, confusion, dizziness, twitching/trembling, and dyspnea. The results are discussed in the context of patient (having a diagnosis of PD) and panic effects (rated as panicking to a challenge).

Acute Disease↗
PubMed2001

Emetophobia: preliminary results of an internet survey.

Through electronic mail, we surveyed members of an internet support group for emetophobia (fear of vomiting). Respondents were 50 women and 6 men with a mean age of 31 years. Results suggest that, for this sample, emetophobia is a disorder of early onset and chronic course, with highly persistent and intrusive symptoms. Emetophobia is implicated in social, home-marital, and occupational impairment and it causes significant constriction of leisure activities. Nearly half of women avoided or delayed becoming pregnant. About three quarters of respondents have eating rituals or significantly limit the foods they eat. Respondents describe other problems such as depression, panic attacks, social anxiety, compulsions, and frequent history of childhood separation anxiety.

Adolescent↗
PubMed2001

Respiratory variability in panic disorder.

Disordered breathing may play an important role in the pathophysiology of panic disorder. Several studies have now indicated that panic disorder patients have greater respiratory variability than normal controls. In this study, we examine baseline respiratory measures in four diagnostic groups to determine whether greater respiratory variability is specific to panic disorder and whether effective anti-panic treatment alters respiratory variability. Patients with panic disorder, major depression, or premenstrual dysphoric disorder, and normal control subjects underwent two respiratory exposures (5% and 7% CO(2) inhalation), while in a canopy system. Panic disorder patients returned after 12 weeks of either anti-panic medication or cognitive behavioral therapy, and were retested. Normal control subjects were also retested after a period of 12 weeks. Panic disorder patients had significantly greater respiratory variability at baseline than normal control subjects and patients with major depression. The premenstrual dysphoric patients also had greater variability than the normal control group. Panic disorder patients who panicked to 7% CO(2) inhalation had significantly greater baseline variability than panic disorder patients who did not panic. Anti-panic treatment did not significantly alter baseline respiratory variability. Our data suggest that increased respiratory variability may be an important trait feature for some panic disorder patients and may make them more vulnerable to CO(2)-induced panic.

Adult↗
PubMed2001

No association or linkage between polymorphisms in the genes encoding cholecystokinin and the cholecystokinin B receptor and panic disorder.

Growing animal data implicate cholecystokinin in the regulation of anxiety, while human clinical research confirms the role of cholecystokinin in the provocation of panic attacks. Antipanic medications suppress the ability of cholecystokinin to induce panic attacks, and may alter the expression of the cholecystokinin gene. Thus, there is increased interest in understanding the molecular genetic component of these observations. Recent association studies using persons with panic disorder described some association between polymorphisms in the genes encoding cholecystokinin and the cholecystokinin B-receptor and panic disorder. In this study, we used a family-based design, employing 596 individuals in 70 panic disorder pedigrees, as well as 77 haplotype relative risk 'triads'. Subjects were genotyped for two polymorphisms: the polymorphic microsatellite marker in the CCK-BR locus using PCR-based genotyping and at a single nucleotide polymorphism in the CCK promoter using a fluorescence polarization detection assay, and the data were analyzed for genetic association and linkage. Employing a variety of diagnostic and genetic models, linkage analysis produced no significant lod scores at either locus. Family-based tests of association, the haplotype-based haplotype relative risk statistic and the transmission disequilibrium test, were likewise non-significant. The results reported here provide little support for the role of these polymorphisms in panic disorder.

Cholecystokinin↗
PubMed2001

Specificity of panic response to CO(2) inhalation in panic disorder: a comparison with major depression and premenstrual dysphoric disorder.

OBJECTIVE: The behavioral response to CO(2) inhalation has been used to differentiate panic disorder patients from normal subjects and other clinical populations. This study extended examination of the diagnostic specificity of CO(2)-induced anxiety by testing panic disorder patients and clinical populations with reported low and high sensitivity to CO(2) inhalation (patients with major depression and patients with premenstrual dysphoric disorder, respectively). METHOD: The behavioral responses to inhalation of 5% and 7% CO(2), administered by means of a respiratory canopy, were studied in 50 patients with panic disorder, 21 with major depression, and 10 with premenstrual dysphoric disorder and in 34 normal comparison subjects. Occurrence of panic attacks was judged with DSM-IV criteria by a blind rater. Subjects were rated on three behavioral scales at baseline and after each CO(2) inhalation. RESULTS: Panic disorder patients had a higher rate of CO(2)-induced panic attacks than depressed patients and normal subjects, whose panic rates were not distinguishable. The panic rate for patients with premenstrual dysphoric disorder was similar to that for panic disorder patients and higher than that for normal subjects. Subjects with CO(2)-induced panic attacks had similarly high ratings on the behavioral scales, regardless of diagnosis, including the small number of panicking normal subjects. Seven percent CO(2) was a more robust panicogen than 5%, and response to 7% CO(2 )better distinguished panic disorder patients from normal subjects than response to 5% CO(2). CONCLUSIONS: Patients with panic disorder and patients with premenstrual dysphoric disorder are highly susceptible to CO(2)-induced panic attacks, and depressed patients appear to be insensitive to CO(2) inhalation. The symptoms of CO(2)-induced panic attacks have a similar intensity regardless of the subject's diagnosis.

Administration, Inhalation↗
PubMed2000

Association between cigarette smoking and anxiety disorders during adolescence and early adulthood.

CONTEXT: Cigarette smoking is associated with some anxiety disorders, but the direction of the association between smoking and specific anxiety disorders has not been determined. OBJECTIVE: To investigate the longitudinal association between cigarette smoking and anxiety disorders among adolescents and young adults. DESIGN: The Children in the Community Study, a prospective longitudinal investigation. SETTING AND PARTICIPANTS: Community-based sample of 688 youths (51% female) from upstate New York interviewed in the years 1985-1986, at a mean age of 16 years, and in the years 1991-1993, at a mean age of 22 years. MAIN OUTCOME MEASURE: Participant cigarette smoking and psychiatric disorders in adolescence and early adulthood, measured by age-appropriate versions of the Diagnostic Interview Schedule for Children. RESULTS: Heavy cigarette smoking (>/=20 cigarettes/d) during adolescence was associated with higher risk of agoraphobia (10.3% vs 1.8%; odds ratio [OR], 6.79; 95% confidence interval [CI], 1.53-30.17), generalized anxiety disorder (20.5% vs 3.71%; OR, 5.53; 95% CI, 1.84-16.66), and panic disorder (7.7% vs 0.6%; OR, 15.58; 95% CI, 2.31-105.14) during early adulthood after controlling for age, sex, difficult childhood temperament; alcohol and drug use, anxiety, and depressive disorders during adolescence; and parental smoking, educational level, and psychopathology. Anxiety disorders during adolescence were not significantly associated with chronic cigarette smoking during early adulthood. Fourteen percent and 15% of participants with and without anxiety during adolescence, respectively, smoked at least 20 cigarettes per day during early adulthood (OR, 0.88; 95% CI, 0.36-2.14). CONCLUSION: Our results suggest that cigarette smoking may increase risk of certain anxiety disorders during late adolescence and early adulthood. JAMA. 2000;284:2348-2351.

Adolescent↗
PubMed2000

Investigation of dopamine receptor (DRD4) and dopamine transporter (DAT) polymorphisms for genetic linkage or association to panic disorder.

Clinical and animal studies suggest a role for the neurotransmitter dopamine in anxiety states. In humans, one such condition is panic disorder, which is typified by recurrent panic attacks accompanied by anticipatory anxiety. Family, segregation, and twin studies imply a genetic component to the pathophysiology of panic disorder. In this study, we examined the genes for the D4 dopamine receptor (DRD4) and the dopamine transporter (DAT) using three common sequence polymorphisms. Two of these polymorphisms were in DRD4, a 12 base-pair insertion/deletion in exon 1 and a 48 base-pair repeat in exon 3, and the third was a 40 base-pair repeat in the 3' untranslated region of DAT. We employed a family-based design, using 622 individuals in 70 families, as well as 82 haplotype relative risk "trios". Subjects were genotyped at the polymorphic loci, and the data were analyzed for genetic association and linkage. There were no significant differences in allele frequencies or occurrence of genotypes within the triads for any of the three polymorphisms. No significant linkage between the DRD4 or DAT polymorphisms and panic disorder was observed in the multiplex families, using a variety of simulations for dominant and recessive models of inheritance. However, LOD scores of approximately 1.1 and 1.05 were observed for the DAT and DRD4 exon 1 loci, respectively. The results reported here provide little support for the role of these polymorphisms in panic disorder.

Alleles↗
PubMed2000

Differential carbon dioxide sensitivity in childhood anxiety disorders and nonill comparison group.

BACKGROUND: To examine the relationship between respiratory regulation and childhood anxiety disorders, this study considered the relationship between anxiety disorders and symptoms during carbon dioxide (CO(2)) exposure, CO(2) sensitivity in specific childhood anxiety disorders, and the relationship between symptomatic and physiological responses to CO(2). METHODS: Following procedures established in adults, 104 children (aged 9-17 years), including 25 from a previous study, underwent 5% CO(2) inhalation. The sample included 57 probands with an anxiety disorder (social phobia, generalized anxiety disorder, separation anxiety disorder, and panic disorder) and 47 nonill comparison subjects. Symptoms of anxiety were assessed before, during, and after CO(2) inhalation. RESULTS: All children tolerated the procedure well, experiencing transient or no increases in anxiety symptoms. Children with an anxiety disorder, particularly separation anxiety disorder, exhibited greater changes in somatic symptoms during inhalation of CO(2)-enriched air, relative to the comparison group. During CO(2) inhalation, symptom ratings were positively correlated with respiratory rate increases, as well as with levels of tidal volume, minute ventilation, end-tidal CO(2), and irregularity in respiratory rate during room-air breathing. CONCLUSIONS: Childhood anxiety disorders, particularly separation anxiety disorder, are associated with CO(2) hypersensitivity, as defined by symptom reports. Carbon dioxide hypersensitivity is associated with physiological changes similar to those found in panic disorder. These and other data suggest that certain childhood anxiety disorders may share pathophysiological features with adult panic disorder.

Adolescent↗
PubMed2000

A method to quantify rater bias in antidepressant trials.

Some studies indicate that the blind in clinical trials of the efficacy of antidepressant drugs is less than perfect. It has been suggested that, as a consequence of this incomplete blind, biased raters inflate efficacy and that, in fact, these drugs are relatively ineffective. However, in the literature, we could find no prior attempt to quantify rater bias and, thus, measure its contribution to claims of antidepressant efficacy. We used the distribution of SCL-90 (Symptom Check List) depression scale scores to derive a patient-based effect size, and contrasted this with the clinician-based effect size. We propose the difference between these two effect sizes (patient self-rating and clinician-derived) to be an indirect measure of bias. If patients had a prodrug bias, this method would be invalid. However the response rate from studies with active placebo suggest a patient prodrug bias is unlikely. The effect sizes derived from patient self-ratings are smaller than those derived from clinician ratings. This allows for the possibility that some clinician ratings were biased. However, quantifying the effect of bias suggests that it was insufficient to invalidate the original study conclusions based on clinician ratings, because the proportion of responders, based on patient self-ratings, differed significantly between the two drugs and placebo. Their 95% confidence intervals (CI) did not overlap. This analysis allows that some clinician ratings may be biased. However, the extent of bias appears insufficient to alter conclusions based on clinician ratings regarding efficacy of antidepressant drugs in this trial. Application of our approach in other trials is necessary to establish generalizability.

Antidepressive Agents↗
PubMed2000

Validity of clinical trials of antidepressants.

OBJECTIVE: Recent reports have criticized the design of antidepressant studies and have questioned their validity. These critics have concluded that antidepressants are no better than placebo treatment and that their illusory superiority depends on methodologically flawed studies and biased clinical evaluations. It has been suggested that the blind in randomized trials is penetrable-since clinician's guesses exceed chance-and that only active placebo can appropriately camouflage the difference between drug and placebo response. Furthermore, evidence has been cited to suggest that psychotherapy is as effective as antidepressants in both the acute and maintenance treatment of depression. These positions are often accepted as valid and have been broadly discussed in both the lay press and scientific literature. The purpose of this review is to reassess the cited data that support these assertions. METHOD: The authors examined the specific studies that were cited in these reports, evaluated their methodology, and conducted aggregate analyses. RESULTS: Analyses of the original sources failed to substantiate 1) that standard antidepressants are no more effective than placebo, 2) that active placebo offers an advantage over inactive placebo, or 3) that substantial evidence of a medication bias is suggested by raters' treatment guesses exceeding chance. The authors also note that some researchers have suggested that the interpretation of psychotherapy trials can be complicated by "allegiance effects." CONCLUSIONS: The issue of bias or allegiance effects for both antidepressant and psychotherapy research is real. Investigators of all orientations must guard against potential bias. However, studies cited as supporting the questionable validity of antidepressant trials fail upon closer examination to support assertions that these trials are invalid.

Antidepressive Agents↗
PubMed2000

A placebo-controlled study of fluoxetine versus imipramine in the acute treatment of atypical depression.

OBJECTIVE: The atypical subtype of depression appears to be both well validated and common. Although monoamine oxidase inhibitors are effective in treating atypical depression, their side effects and prescription-associated dietary restrictions reduce their suitability as a first-line treatment. The objective of this study was to estimate the efficacy of the selective serotonin reuptake inhibitor (SSRI) fluoxetine in the treatment of major depression with atypical features. METHOD: One hundred fifty-four subjects with DSM-IV major depression who met the Columbia criteria for atypical depression were randomly assigned to receive fluoxetine, imipramine, or placebo for a 10-week clinical trial. Imipramine was included because its known efficacy for treatment of atypical depression helped to calibrate the appropriateness of the study group. RESULTS: In both intention-to-treat and completer groups, the effectiveness of both fluoxetine and imipramine was significantly better than that of placebo. The two medications did not differ from each other in effectiveness. Significantly more patients dropped out of treatment with imipramine than with fluoxetine. Before treatment, patients on average rated themselves as very impaired on psychological dimensions of general health and moderately impaired on physical dimensions, compared with population norms. The self-ratings of patients who responded to treatment essentially normalized on these measures. CONCLUSIONS: Despite earlier data that SSRIs might be the treatment of choice, fluoxetine appeared to be no better than imipramine in the treatment of atypical depression, although fluoxetine was better tolerated than imipramine.

Adolescent↗
PubMed2000

Barriers to the treatment of social anxiety.

OBJECTIVE: This article evaluates barriers to treatment reported by adults with social anxiety who participated in the 1996 National Anxiety Disorders Screening Day. METHOD: The background characteristics of screening day participants with symptoms of social anxiety (N=6,130) were compared with those of participants without social anxiety (N=4,507). Barriers to previous mental health treatment reported by participants with and without symptoms of social anxiety were compared. RESULTS: Social anxiety was strongly associated with functional impairment, feelings of social isolation, and suicidal ideation. Compared to participants without social anxiety, those with social anxiety were significantly more likely to report that financial barriers, uncertainty over where to go for help, and fear of what others might think or say prevented them from seeking treatment. However, they were significantly less likely to report they avoided treatment because they did not believe they had an anxiety disorder. Roughly one-third (N=1,400 of 3,682, 38.0%) of the participants with symptoms of social anxiety who were referred for further evaluation were specifically referred for an evaluation for social phobia. CONCLUSIONS: Social anxiety is associated with a distinct pattern of treatment barriers. Treatment access may be improved by building public awareness of locally available services, easing the psychological and financial burden of entering treatment, and increasing health care professionals' awareness of its clinical significance.

Adult↗