A subcomplex of three eIF3 subunits binds eIF1 and eIF5 and stimulates ribosome binding of mRNA and tRNA(i)Met.

Yeast translation initiation factor 3 contains five core subunits (known as TIF32, PRT1, NIP1, TIF34 and TIF35) and a less tightly associated component known as HCR1. We found that a stable subcomplex of His8-PRT1, NIP1 and TIF32 (PN2 subcomplex) could be affinity purified from a strain overexpressing these eIF3 subunits. eIF5, eIF1 and HCR1 co-purified with this subcomplex, but not with distinct His8-PRT1- TIF34-TIF35 (P45) or His8-PRT1-TIF32 (P2) sub complexes. His8-PRT1 and NIP1 did not form a stable binary subcomplex. These results provide in vivo evidence that TIF32 bridges PRT1 and NIP1, and that eIFs 1 and 5 bind to NIP1, in native eIF3. Heat-treated prt1-1 extracts are defective for Met-tRNA(i)Met binding to 40S subunits, and we also observed defective 40S binding of mRNA, eIFs 1 and 5 and eIF3 itself in these extracts. We could rescue 40S binding of Met- tRNA(i)Met and mRNA, and translation of luciferase mRNA, in a prt1-1 extract almost as well with purified PN2 subcomplex as with five-subunit eIF3, whereas the P45 subcomplex was nearly inactive. Thus, several key functions of eIF3 can be carried out by the PRT1-TIF32-NIP1 subcomplex.

Related eIF3 subunits TIF32 and HCR1 interact with an RNA recognition motif in PRT1 required for eIF3 integrity and ribosome binding.

eIF3 binds to 40S ribosomal subunits and stimulates recruitment of Met-tRNAiMet and mRNA to the pre-initiation complex. Saccharomyces cerevisiae contains an ortholog of human eIF3 subunit p35, HCR1, whose interactions with yeast eIF3 are not well defined. We found that HCR1 has a dual function in translation initiation: it binds to, and stabilizes, the eIF3-eIF5- eIF1-eIF2 multifactor complex and is required for the normal level of 40S ribosomes. The RNA recognition motif (RRM) of eIF3 subunit PRT1 interacted simultaneously with HCR1 and with an internal domain of eIF3 subunit TIF32 that has sequence and functional similarity to HCR1. PRT1, HCR1 and TIF32 were also functionally linked by genetic suppressor analysis. We propose that HCR1 stabilizes or modulates interaction between TIF32 and the PRT1 RRM. Removal of the PRT1 RRM resulted in dissociation of TIF32, NIP1, HCR1 and eIF5 from eIF3 in vivo, and destroyed 40S ribosome binding by the residual PRT1-TIF34-TIF35 subcomplex. Hence, the PRT1 RRM is crucial for the integrity and ribosome-binding activity of eIF3.

The current status of psychological assessment training in graduate and professional schools.

Test-based psychological assessment is threatened by the policies of managed care organizations; however, research has demonstrated that test-based psychological assessment is quite valuable and economically justified when conducted by well-trained psychologists. This surfaces the question of the current status of graduate training in test-based psychological assessment. Results of this study indicate that clinical and counseling students currently receive almost equivalent training in test-based assessment. However, in a larger context, results indicate a lack of sound preparation in test-based assessment training for a large proportion of clinical and counseling students. These findings are discussed in terms of their implications for the field and, more specifically, for graduate and internship training.

Pituitary adenylate cyclase-activating polypeptide innervation of the mudpuppy cardiac ganglion.

The presence and potential origin of the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) was determined in cardiac ganglia of the mudpuppy, Necturus maculosus. Although PACAP has been implicated in the regulation of cardiac function in several mammalian species, the presence of this peptide in the autonomic nervous system (ANS) of other species is unclear. Thus, this study is the first to characterize this highly conserved peptide in the ANS of a non-mammalian species. PACAP-immunoreactivity was observed in nerve fibers throughout the mudpuppy cardiac ganglia and often was co-localized with the sensory neuropeptides substance P and calcitonin gene-related peptide. Removal of all extrinsic inputs to the ganglia by organ culture eliminated PACAP-immunoreactivity in the cardiac ganglia, whereas bilateral vagotomies only partially reduced PACAP-labeling. PACAP-immunoreactive neurons were observed in both high thoracic dorsal root ganglia and in vagal sensory ganglia. While no PACAP-positive neurons were observed in caudal medulla brainstem regions, PACAP-containing nerve fibers were found in the region of the nucleus solitarius. These results suggest that, in the mudpuppy, PACAP is found primarily in visceral afferent fibers, originating from cells in either the dorsal root ganglia or vagal sensory ganglia. Based on their anatomic localization, these afferent fibers may function to transmit important sensory information to cardiovascular centers in the brain as well as serving as local reflex inputs to modulate postganglionic parasympathetic output within the cardiac ganglion itself.

Endoscopic spray cryotherapy: a new technique for mucosal ablation in the esophagus.

BACKGROUND: A simple and safe method for controlled ablation of esophageal mucosa is not currently available. Therefore, an endoscopic cryotherapy device was developed and its efficacy and safety were assessed in a swine model. METHODS: The device consists of a cryogenic system that delivers cold nitrogen gas via a catheter introduced into the esophagus through the accessory channel of an upper GI endoscope. Esophagoscopy was performed in 20 swine under conscious sedation, and cold nitrogen gas was sprayed on the distal 2 to 3 cm of the esophagus under direct visualization. RESULTS: Freezing of the esophageal mucosa was evidenced by the appearance of a white "cryoburn" with sharply demarcated margins. Hemicircumferential to circumferential freezing of the distal esophagus was achieved in 20 swine by varying the duration of cryoburn from 10 to 60 seconds. Mucosal ablation was noted 2 to 7 days after treatment in 95% of the swine. Complications included 3 esophageal strictures and 1 aspiration pneumonia. CONCLUSIONS: Cryotherapy performed by spraying liquid nitrogen at upper GI endoscopy is a simple technique capable of inducing controlled superficial mucosal necrosis with complete healing in the esophagus. This method warrants further evaluation as a treatment for esophageal lesions including Barrett's esophagus.

A technique for evaluating cast foam positioning and immobilization devices used in breast cancer radiotherapy.

Patient setup reproducibility when Alpha Cradles* are used is not well documented. A simple technique is described that localizes longitudinal and transverse planes in breast setups utilizing 4 mm lead-sphere markers embedded in a modified HS-2 Alpha Cradle. The markers are positioned in the cradle coincident with the projected simulator central axis crosshair when the x-ray beam is directed vertically down through a setup point on the patient. A reference film recording patient position relative to the Alpha Cradle is taken through the setup point at the end of the simulation procedure. On the treatment machine, the images of the lead markers on the portal film, taken through the same setup point, indicate longitudinal and transverse planes. These planes are then used to correlate and quantitate the reproducibility of the original reference planes. This technique is easily initiated, and when used in conjunction with a careful analysis of conventional treatment portal films, is very useful in determining the accuracy of patient repositioning in the Alpha Cradle, and precise field placement. Results of a study utilizing a modified HS-2 Alpha Cradle will be presented.

Anger and hostility in tension-type headache.

A battery of standardized psychometric tests was administered to a group of 47 episodic tension-type headache sufferers and 47 headache-free controls. Compared to controls, headache subjects showed higher levels of anxiety, depression, and anger/hostility. The groups did not differ significantly on a measure of anger expressed toward persons or objects, but headache subjects showed significantly greater levels of suppressed anger. The results provide objective data that are in general agreement with predictions derived from psychosomatic theories about the interrelationships among anxiety,

Intravenous regional sympatholysis: a double-blind comparison of guanethidine, reserpine, and normal saline.

This double-blind, randomized study was designed to compare the effectiveness of intravenous regional sympatholysis using guanethidine, reserpine and normal saline. Twenty-one patients with reflex sympathetic dystrophy of an upper or lower extremity were enrolled and received intravenous regional blockade (IVRB) with one of the three medications. There was significant pain relief in all three groups at 30 min. There were no significant differences among the three groups in the degree of pain relief, the number of patients obtaining pain relief in the 30 min after the block, or the number of patients reporting more than 50% pain relief for more than 24 hr. The saline group's high rate of pain relief could be partially due to a mechanism of tourniquet-induced analgesia.

A controlled trial of transcutaneous electrical nerve stimulation (TENS) and exercise for chronic low back pain.

A number of treatments are widely prescribed for chronic back pain, but few have been rigorously evaluated. We examined the effectiveness of transcutaneous electrical nerve stimulation (TENS), a program of stretching exercises, or a combination of both for low back pain. Patients with chronic low back pain (median duration, 4.1 years) were randomly assigned to receive daily treatment with TENS (n = 36), sham TENS (n = 36), TENS plus a program of exercises (n = 37), or sham TENS plus exercises (n = 36). After one month no clinically or statistically significant treatment effect of TENS was found on any of 11 indicators of outcome measuring pain, function, and back flexion; there was no interactive effect of TENS with exercise. Overall improvement in pain indicators was 47 percent with TENS and 42 percent with sham TENS (P not significant). The 95 percent confidence intervals for group differences excluded a major clinical benefit of TENS for most outcomes. By contrast, after one month patients in the exercise groups had significant improvement in self-rated pain scores, reduction in the frequency of pain, and greater levels of activity as compared with patients in the groups that did not exercise. The mean reported improvement in pain scores was 52 percent in the exercise groups and 37 percent in the nonexercise groups (P = 0.02). Two months after the active intervention, however, most patients had discontinued the exercises, and the initial improvements were gone. We conclude that for patients with chronic low back pain, treatment with TENS is no more effective than treatment with a placebo, and TENS adds no apparent benefit to that of exercise alone.

Can trials of physical treatments be blinded? The example of transcutaneous electrical nerve stimulation for chronic pain.

Therapeutic trials often attempt to "blind" patient and investigator to the true nature of treatments received, reducing the influences of conscious or subconscious prejudices. In drug trials, this is accomplished with placebo tablets, but blinding in trials of physical treatments is more problematic. This issue arose in a clinical trial of transcutaneous electrical nerve stimulation (TENS) for patients with chronic low back pain. Several study design features were incorporated to promote blinding: use of sham TENS units visually identical with real units, exclusion of potential subjects with previous TENS experience, avoidance of a crossover design and use of identical visit frequency, instructions and modifications in electrode placement. Subjects were asked not to discuss treatments with the clinicians who performed outcome assessments. Both patients and clinicians were asked to guess actual treatment assignments at the trial's end. Every patient in the true TENS group believed the unit was functioning properly, but the degree of certainty varied. In the sham TENS group, 84% also believed they had functioning units, but their certainty was significantly less than in the active treatment group. Differences in patient perceptions did not affect compliance, as the two groups had similar dropout rates, appointment compliance, days of TENS use and daily duration of TENS use. Clinicians guessed treatments correctly 61% of the time (as opposed to 50% expected by chance), again suggesting partial success in blinding. These efforts at blinding may partly explain the negative trial results for TENS efficacy. We conclude that complete blinding is difficult to achieve because of sensory difference in treatment and unintended communication between patient and examiner.(ABSTRACT TRUNCATED AT 250 WORDS)

Psychosexual study of women with detrusor instability.

Clinical impression suggests that many cases of detrusor instability are psychosomatic. We evaluated 63 women with urinary incontinence and 27 continent controls using the Minnesota Multiphasic Personality Inventory, Uplift and Hassle Scales, and a structured questionnaire screening sexual dysfunction. All incontinent women underwent diagnostic urodynamic studies including uroflowmetry, subtracted water cystometry with provocation, and urethral closure pressure profilometry. Thirty-five women had genuine stress incontinence and 28 had detrusor instability, including nine with mixed incontinence. No differences in psychological test results were noted between the detrusor-instability and genuine-stress-incontinence groups. On the Minnesota Multiphasic Personality Inventory, subjects with detrusor instability scored significantly higher than controls on the hypochondriasis (P = .006), depression (P = .01), and hysteria (P = .0009) scales. Compared with continent controls, the detrusor-instability group reported a lower frequency of uplifts (P less than .05) and a greater intensity of hassles (P less than .05). Both incontinent groups reported more sexual dysfunction than did controls. We conclude that many women with urinary incontinence have abnormal psychological and sexual test results reflecting moodiness, feelings of helplessness and sadness, pessimism, general hypochondriasis/somatization, and sexual dysfunction. These abnormalities appear to be associated with urinary incontinence in general rather than with specific diseases of the urinary tract.

Diagnostic epidural opioid technique.

Diagnostic epidural blocks were performed on 27 chronic pain patients sequentially using saline, fentanyl, and lidocaine solution. The patients were divided into one of four groups based on their response to the epidural solutions: placebo response group--pain relief with placebo solutions; fentanyl response group--pain relief with epidural fentanyl; lidocaine response group (LRG)--pain relief with lidocaine but not fentanyl; and no response group--no pain relief with any of the solutions used. The four groups were compared on the basis of age, sex, site of pain, duration of pain, narcotic use, pain assessment index, and workmen's compensation claims. The comparisons resulted in the conclusion that LRG patients had a much longer average duration of pain than the other groups. On the basis of the information gathered, it was theorized that, despite their response to epidural lidocaine, LRG patients may actually be a group of operant pain patients. Their failure to receive analgesia from epidural fentanyl may be a learned response such that they associate any sensory input from the affected area as painful. If follow-up studies support these findings, then the diagnostic opioid technique may be a more sensitive tool in diagnosing chronic pain.

Evaluation of neurolytic blocks using phenol and cryogenic block in the management of chronic pain.

This study compared the use of phenol and cryogenic blocks for neurolysis in 28 patients. Patients were assigned randomly to receive peripheral nerve blocks with either phenol or cryoanalgesia. Significantly more patients in the phenol group received 20% or greater relief at 2, 12, and 24 wk than patients in the cryogenic group. Only 27% of patients received significant relief, however, indicating that neurolytic blocks were not particularly effective even though local anesthetic blocks produced significant but temporary pain relief.

Studies of the Modified Somatic Perceptions Questionnaire (MSPQ) in patients with back pain. Psychometric and predictive properties.

The Modified Somatic Perceptions Questionnaire (MSPQ) was designed to measure heightened somatic awareness among patients with chronic pain. It was hoped that this questionnaire would help predict therapeutic responses for back pain patients. The reliability, validity, and predictive characteristics of this scale were tested among 97 patients with chronic low-back pain enrolled in a clinical trial of transcutaneous nerve stimulation and stretching exercises. Internal consistency was good (alpha = 0.78), and correlations with the Zung depression scale and certain MMPI scales were significant. Correlations with a baseline functional scale (the Sickness Impact Profile) were stronger than those with the MMPI. Unfortunately, the MSPQ did not correlate with functional outcomes, and was only weakly associated with pain outcomes. Thus, the MSPQ appears to be reliable and valid, but the somatic perceptions it measures may have little relation to patient outcomes.

Normative model for cold pressor test.

The cold pressor test elicits an emotional/motivational pain experience from the immersion of a limb in cold water. It has been widely used to evaluate (experimental and chronic) pain. However, normative models for quantification and comparison for pain tolerance have not previously been established. This study developed a normative mathematical model for pain tolerance using the cold pressor test with over 600 subjects. Norms for age, sex, and ethnic group were calculated. In addition, chronic pain patients were compared with pain-free patients to determine normative differences in response. The results indicate that at any given age Anglo-Saxon males have the longest tolerance time followed by non-Anglo-Saxon males, Anglo-Saxon females, and finally non-Anglo-Saxon females. There is a consistent decrease in tolerance time as the male age increases and minimal change in tolerance time as the female age increases. Chronic pain patients exhibited the same type of pain response pattern as healthy volunteers when corrected for age, sex, and ethnocultural subgroup.

Sociodemographic and clinical correlates of P-A-I-N.

Rules to clarify MMPI profiles into four types (P-A-I-N) observed commonly in chronic pain patient populations were tested to determine if resulting average profiles matched computer-algorithm derived prototypes. Close matches were obtained, suggesting that the rules could be used in the ordinary pain clinic setting to look for type x treatment interactions. Seven clinical variables differentiated the types. Type P and N were most different from one another, and Types A and I represented poles on an optimism-pessimism dimension.

Prognostic variability among chronic pain patients: implications for study design, interpretation, and reporting.

Chronic pain patients share many characteristics, but there is important prognostic variability among them. By selecting for certain characteristics, different recruitment methods and entry criteria for clinical or research programs may influence the likelihood of success regardless of treatment efficacy. This was demonstrated when subjects (n = 55) were recruited through lay publicity for a clinical trial of therapy for chronic back pain. In comparison to routine pain clinic patients (n=61), subjects in the clinical trial were better educated, were more often employed, had more favorable personality profiles, and were less likely to have had surgery or narcotic use (all p less than 0.004). Pain relief was significantly better for clinical trial subjects, apparently due to baseline prognostic differences rather than uniquely efficacious therapy. We conclude that chronic pain patients vary in prognostically important ways; that recruitment methods and criteria strongly influence these characteristics; and that greater attention to these details is needed when interpreting and reporting clinical research.

Analgesic effectiveness of D-phenylalanine in chronic pain patients.

Enkephalins are a biochemical pathway for endogenous analgesia. A number of compounds inhibit degradation of enkephalins within the body. One of these compounds, D-phenylalanine (DPA), has been shown to increase the pain threshold in animals. It is hypothesized that this naloxone reversible analgesia is induced by DPA blockage of enkephalin degradation by the enzyme carboxypeptidase A. Preliminary studies of chronic pain patients have shown a response rate to DPA from 32% to 75%. This study was a double-blind crossover evaluation of a randomized parallel design to determine the efficacy of DPA in 30 subjects with chronic pain from varied etiology which was unrelieved by multiple therapeutic interventions. Each patient received a stabilized therapeutic regimen during this study consisting of four weeks of either DPA 250 mg or lactose (placebo) orally four times a day. After four weeks the DPA and placebo groups were crossed over for an additional four weeks of treatment. Pain was quantified using a visual analog pain scale and a cold pressor test. Data from the pain questionnaires revealed more pain relief on DPA reported by 25% of the patients, more pain relief on placebo reported by 22% of the patients, and no difference in pain relief reported by 53% of the patients. Lowest pain level of the visual analog scale was reported by 47% of the patients on DPA and 53% on placebo. There appears to be no significant analgesic effect from D-phenylalanine in chronic pain patients when compared to placebo.