Conditioned narcotic withdrawal in humans.

Subjective and physiological manifestations of the narcotic withdrawal syndrome were produced as a conditioned response. Withdrawal reactions precipitated by the narcotic antagonist naloxone in methadone-dependent volunteers were the unconditioned response. These data support clinical anecdotes of withdrawal symptoms occurring in former addicts when they return to their drug-related environment.

Stuttering, dichotic listening, and cerebral dominance.

Fully right-sided stutterers (35) and fully right-sided nonstutterers (35) had a dichotic listening task to test hypotheses that stutterers have incomplete cerebral lateralization or reversed lateralization of speech function, or both. An assumption of the procedure is that a right-ear preference indicates left-cerebral dominance for speech. Six stutterers and no nonstutterers showed a reversal, ie, a left-ear preference. As a group, the remaining stutterers who showed no such reversal were the same as nonstutterers in the magnitiude of the right-ear preference. This suggests that a subset of stutterers may have an anomaly in the lateralization of speech functions. A nonsignificant tendency emerged for stutterers to show smaller between-ear differences on the test, consistent with the hypothesis that stutterers have less or incomplete lateralization of speech function than nonstutterers.

The acute effect of haloperidol and apomorphine on the severity of stuttering.

In studies of the acute effects of haloperidol on the severity of stuttering in 12 subjects not in treatment at the time of drug evaluation, a single 0.5 mg haloperidol injection was found to increase fluency in 9 to 12 subjects, as compared with saline placebo. The average improvement in those subjects who improved was 25% on reading and 40% on spontaneous speech. Side effects from this dose of haloperidol were minimal. The effects of apomorphine on speech were not statistically significant, but increased fluency was seen in a number of subjects on the reading test. The results of this study suggest that acute drug evaluation studies may be valuable in determining the effects of various psychotropic agents on the severity of stuttering. The increased fluency after haloperidol, an agent which is felt to turn off the dopaminergic system via postsynaptic blockade, and after low-dose apomorphine, which appears to inhibit the dopamine system via presynaptic effects is consistent with a role for central dopaminergic systems in the pathogenesis of stuttering. Further studies are needed to confirm this hypothesis.

Cloning and characterization of a novel zinc-finger protein-encoding cDNA from the mouse eye lens.

Zinc fingers (Zf) are a common structural motif found in many nucleic acid-binding proteins. In an effort to identify potential transcription factors in the mouse eye lens, we have isolated a Zf-containing clone from a newborn mouse lens cDNA library. The clone, named pMLZ-4, is 4.5 kb in length and contains an open reading frame of 1073 bp. The putative pMLZ-4 protein consists of a short, N-terminal acidic domain followed by twelve tandemly arrayed Zf of the C2H2 variety. The remaining 3.2 kb of the cDNA comprises the 3'-untranslated region. PCR analysis detected the presence of pMLZ-4 RNA in liver, heart, kidney, spleen and brain of newborn mice. Hybridization of pMLZ-4 to genomic DNA from a number of species of vertebrates revealed the presence of homologous sequences only in mouse and rat. Unexpectedly, the probe also hybridized to a single band in yeast DNA digested with EcoRI. NIH3T3 cells were stably transformed with a construct that over-expresses the pMLZ-4 mRNA. The stably transformed cells did not differ in appearance from untransformed cells, and an analysis of proteins from transformed and untransformed cells failed to detect any differences resulting from over-expression of the pMLZ-4 mRNA.

A mouse cDNA encoding a protein with zinc-fingers and a KRAB domain shows similarity to human profilaggrin.

As part of our efforts to understand transcriptional regulation in the vertebrate eye lens, we have isolated a clone that encodes a zinc finger (Zf) protein from a newborn mouse lens cDNA library. Corresponding message for this protein is detectable in the lens, liver, heart, kidney, spleen and brain of newborn mice. A longer cDNA containing the complete ORF for the same protein was isolated from an adult mouse testis library. A conceptual translation of the testis cDNA sequence produces a 555-amino-acid (aa) protein that contains nine C-terminal Zf and an N-terminal domain found in a subset of C2H2 Zf, the Krüppel-associated box (KRAB). The aa sequence located between the KRAB domain and the Zf shows an unexpected similarity to human profilaggrin, a protein expressed in differentiating epidermal cells. Sequences that hybridize to this cDNA are detectable in ten other mammalian species.

Social skills training for psychiatric patients. I: Concepts, methods, and clinical results.

Deficits in social skills are often seen in psychiatric patients. In particular instances these may be a consequence of the psychiatric illness, a contributing cause to that illness, or a feature of the psychiatric disorder. During the last two decades, systematic training programs in social skills have been developed and evaluated for the amelioration of these deficiencies. The author critically reviews basic concepts and methods in social skills training and the results of treatment in case reports, analogue studies, and single-case experimental designs.

Social skills training for psychiatric patients, II: Clinical outcome studies.

In this second paper on social skills training for psychiatric patients the author critically reviews the controlled clinical outcome studies of social skills training in a number of psychiatric populations: mentally retarded persons, depressed patients, psychiatric outpatients, and psychiatric inpatients. He points out that more research is needed to determine the effectiveness of social skills training, especially for patients with debilitating chronic mental illness.

The pharmacology of stuttering: a critical review.

OBJECTIVE: The author critically examines the limited world literature on pharmacologic treatments of stuttering. METHOD: The literature on stuttering and drugs was identified by means of two computer-assisted searches. FINDINGS: A great variety of pharmacologic agents have been used to treat stuttering, reflecting the many theories about the origin and nature of the disorder. In some instances new hypotheses about the nature of stuttering have followed the chance discovery of agents having some efficacy. CONCLUSIONS: Few studies have used adequate experimental designs. Promising avenues of research, both for the treatment of stuttering and for exploring its nature, include the use of calcium channel blocking agents and cholinergic drugs.

Behavior therapy and sex therapy.

Behavior therapy is characterized by the way in which clinical data are collected, analyzed, and used in the treatment program-specifically, the application of the methods of experimental and social psychology. A case history of the behavioral treatment of a sexual problem is presented to illustrate this process. Many people have assumed that the "new sex therapy" is behavior therapy because of its focus on the here and now and similarities in particular treatment maneuvers. However, the author notes that sex therapy is behavior therapy only to the extent that it deals comprehensively with environmental, interpersonal, and organismic factors that operate to maintain the sexual problem.

Effect of continuous positive airway pressure on the ventilatory response to CO2 in preterm infants.

The effect of continuous positive airway pressure (CPAP) on the ventilatory response to CO2 in newborn infants is unknown. The CO2 response to 4% CO2 in air was studied in nine preterm infants without lung disease before and during administration of CPAP (4 to 5 cm H2O) delivered by face mask. Minute ventilation, tidal volume, respiratory frequency, and end-tidal PCO2 were measured, and the slope and intercept of the CO2 response were calculated. Respiratory pattern and changes in oxygenation were also analyzed by measuring inspiratory and expiratory time, mean inspiratory flow, mean expiratory flow, effective respiratory timing, end-tidal PO2, and transcutaneous PO2. CPAP significantly decreased minute ventilation from 278.7 to 197.6 mL/min/kg (P less than .001). Tidal volume and respiratory frequency were also significantly decreased. The slope of the CO2 response during CPAP was not significantly different from the slope before CPAP (36 v 33 mL/min/kg/mm Hg, P greater than .1), but the intercept was shifted to the right (P less than .001). The decrease in respiratory frequency was primarily due to a prolongation of expiratory time (P less than .05). In addition, transcutaneous PO2 increased during administration of CPAP (P less than .001). These findings indicate that: (1) CPAP significantly decreases ventilation in preterm infants without lung disease, affecting both tidal volume and respiratory frequency; (2) CPAP does not appreciably alter the ventilatory response to CO2; (3) the changes in respiratory frequency are primarily accounted for by a prolongation of expiratory time; (4) CPAP improves oxygenation.

Increased work of breathing associated with nasal prongs.

To see if continuous distending pressure (CPD) given by nasal prongs increases work of breathing, we measured the mechanics of breathing, minute ventilation, and blood gases in nine infants with both nasal prong and face mask CDP. Minute ventilation was 16% larger (P less than .02), work of breathing was 94% higher (P less than .01), and the mean PaO2 was 8 mm Hg lower (P less than .03) with the nasal prongs. There was no difference in pH or PaCO2. We speculate that CDP given by nasal prongs may increase the risk of respiratory failure in the premature infant already compromised with hyaline membrane disease.

Chemoreceptor reflexes in preterm infants: I. The effect of gestational and postnatal age on the ventilatory response to inhalation of 100% and 15% oxygen.

We studied 16 "healthy" preterm infants (birthweight, 1,000 to 2,000 gm) 94 times during postnatal life to define the effect of gestational and postnatal age on the ventilatory response to 100% and 15% oxygen. They were given air, then 100% oxygen for two and five minutes respectively (No.=63) or 21%, 15% and then 21% oxygen for five minutes each (No.=31). We measured respiratory minute and tidal volumes, frequency, heart rate, and alveolar PCO2 and PO2. We used the magnitude of the immediate change in ventilation during during 100% and 15% oxygen breathing to test peripheral chemoreceptor function. The immediate decrease in ventilation with 100% oxygen and the immediate increase in ventilation with 15% oxygen were statistically similar at different gestational and postnatal ages. The late increase in ventilation (five minutes) with 100% oxygen was also similar at different ages. However, the late decrease in ventilation with 15% oxygen was not present at 18 days of age. These findings suggest that: (1) the peripheral chemo-receptors are active at least from 28 weeks of gestation and are probably not important in triggering periodic breathing or apnea in preterm infants, and (2) the preterm infant matures his response to hypoxia and is able to sustain hyperventilation with low oxygen by 18 days of age.

Chemoreceptor reflexes in preterm infants: II. The effect of gestational and postnatal age on the ventilatory response to inhaled carbon dioxide.

We studied nine "healthy" preterm infants (birthweight, 1,000 to 2,000 gm) 58 times during postnatal life to define the effects of gestational and postnatal age on the ventilatory response to carbon dioxide. The infants were given air and 2% and 4% carbon dioxide in air to breathe for five minutes each. We determined respiratory minute and tidal volumes, frequency,heart rate, and alveolar PCO2 and PO2. We measured ventilation with a nosepiece and a screen flowmeter, using a constant flow-through to eliminate valves and reduce diad space. Analysis were made during the fifth minute while the baby breathed the various gas mistures. The slope of the carbon dioxide response increased 42% from 32 to 37 weeks gestation (P smaller than .05) and 62% from 2 to 27 days of age (P smaller than. 025). However, the intercept at .3 liter/min/kg was the same at different gestational ages, but significantly greater at 2 compared with 27 days of age (P smaller than.05). We sugest that the unresposiveness primarily dependent on the mechanical abnormalities of the lung.

Chronic pulmonary disease in neonates after artificial ventilation: distribution of ventilation and pulmonary interstitial emphysema.

To determine pulmonary function abnormalities in patients with neonatal bronchopulmonary dysplasia (BPD), we measured distribution of ventilation by nitrogen washout, minute and tidal volume, and arterial and alveolar gases in three groups of ten preterm infants with similar birth weights (mean = 1,340 g) and gestational ages (mean = 30.3 weeks). Infants in group A were never artificially ventilated, those in group B were ventilated but had no subsequent BPD, and those in group C were ventilated and developed BPD. Infants with BPD had severe maldistribution of ventilation (pulmonary clearance delay 223% versus 47% and 60% for groups A and B). They had decreased tidal volumes (5.3 ml versus 7.0 and 6.2 ml) and higher respiratory rates (60/min versus 47 and 48) but similar minute volumes. They also had increased PaCO2 (53.6 torr versus 41.9 and 43.4 torr) and increased arterial-alveolar carbon dioxide gradients (6.8 torr versus 3.1 and 1.8 torr). There was no statistically significant difference between groups B and C for the time spent in fractional inspired oxygen greater than 0.40 and greater than 0.60, or the time ventilated for intubated, or the incidence of patent ductus arteriosus. Early pulmonary interstitial emphysema was much more common in the infants who subsequently developed BPD (eight of ten versus two of ten, P less than .01).

Apnea, hypoxemia, and aborted sudden infant death syndrome.

To find out whether there is any relationship between the ventilatory response to hypoxia and the sudden infant death syndrome (SIDS), we studied the effects of mild induced hypoxia (PIO2, 120 mm Hg = 17% oxygen) in 16 infants aged 2 weeks to 6 months. Eight had recurrent apneic spells (apnea group) (five had aborted SIDS and three had recurrent apnea in the intensive care nursery) and eight were "well" preterm infants about to fly in a pressurized airplane (PIO2, 120 mm Hg) (control group). Mean birth weights were 2,245 and 1,400 gm and mean gestational ages were 35 and 30 weeks. Postconceptual ages (41.8 and 41.3 weeks) were almost identical. Heart rate was obtained from an ECG, and respiratory rate and pattern were obtained from a pneumogram. In addition, end-tidal PCO2 and PN2 or PO2 were obtained with a nasal catheter and gas analyzers. In the apnea group with inhalation of 17% oxygen, we observed an increase in periodic breathing and an increase in both rate and total duration of respiratory pauses. In the control group there were no significant changes. Heart rate and PCO2 did not change in either group. Our findings suggest that infants prone to apnea may have unique respiratory responses to mild induced hypoxia.

AlphaB-crystallin in lens development and muscle integrity: a gene knockout approach.

PURPOSE: To study the role of alphaB-crystallin (alphaB) in the developing lens and its importance in lens structure and function. METHODS: Gene targeting in embryonic stem cells was used to generate mouse lines in which the alphaB gene and its protein product were absent. Gene structure and expression were characterized by genomic Southern blot, immunoblot, and Northern blot analyses, and two-dimensional gel electrophoresis. The gene knockout mice were screened for cataract with slit lamp biomicroscopy, and dissected lenses were examined with dark-field microscopy. Lenses and other tissues were analyzed by standard histology and immunohistochemistry. Chaperone activity was determined by heating lens homogenate supernatants and measuring absorbance changes. RESULTS: In an unexpected result, lenses in the alphaB gene knockout mice developed normally and were remarkably similar to wild-type mouse lenses. All the other crystallins were present. The thermal stability of a lens homogenate supernatant was mildly compromised, and when oxidatively stressed in vivo with hyperbaric oxygen, the knockout lenses reacted similarly to wild type. In targeting the alphaB gene, the adjacent HSPB2 gene, which is not expressed in the lens, was also disrupted. Loss of alphaB and/or HSPB2 function leads to degeneration of some skeletal muscles. CONCLUSIONS: AlphaB is not essential for normal development of a transparent lens in the mouse, and therefore is more dispensable to the lens than the closely related alphaA-crystallin. It may play a small role in maintaining transparency throughout life. alphaB and/or the closely related HSPB2 is required to maintain muscle cell integrity in some skeletal muscles.

Correction of metabolic acidosis and its effect on albumin in chronic hemodialysis patients.

Serum albumin concentration has been strongly associated with risk of death in hemodialysis patients, with mortality increasing as albumin decreases. Metabolic acidosis stimulates protein catabolism and decreases protein synthesis. A study was undertaken to investigate the effect of increasing predialysis serum bicarbonate (HCO3) concentrations on the nutrition of hemodialysis patients as measured by albumin and total lymphocyte count (TLC). Metabolic acidosis was defined as a predialysis serum bicarbonate concentration of < or = 18 mEq/L. Thirty-six hemodialysis patients were enrolled in the study. Each had been stable on hemodialysis for > or = 3 months and each had a mean serum bicarbonate concentration of < or = 18 mEq/L on predialysis monthly laboratory values during the preceding 3 months. The subjects were randomized into 2 groups. The first group consisted of 18 control subjects who were dialyzed on a standard bicarbonate bath of 35 mEq/L. The second group consisted of 18 experimental patients who were dialyzed on a bicarbonate bath of 40 mEq/L. Subjects in the experimental group who had predialysis serum bicarbonate concentrations less than 22 mEq/L after 2 weeks on the higher bicarbonate bath were additionally supplemented with oral sodium bicarbonate at a dosage of 1 mEq/kg dry weight/d. Monthly predialysis laboratory values were checked for all subjects and included serum electrolytes, blood urea nitrogen, calcium, and albumin. TLCs were obtained at the initiation and at the conclusion of the study. Intact parathyroid hormone, blood pressures, and interdialytic weight gains were also followed. The study lasted 16 weeks; 32 subjects completed the study (16 in each group). There were no statistically significant differences between the two groups at the initiation of the study. The serum bicarbonate concentrations were significantly different between the two groups at the end of the study (control HCO3 17.3 +/- 3.2 mEq/L v experimental HCO3 20.2 +/- 2.9 mEq/L; P = 0.01). Serum albumin concentrations and TLCs were not statistically different (P > 0.05) between the two groups at the end of the study (control albumin 3.88 +/- 0.28 g/dL v experimental albumin 3.76 +/- 0.26 g/dL and control TLC 1,780.0 +/- 779.4/mm3 v experimental TLC 2,020.1 +/- 888.0/mm3). Potassium, intact parathyroid hormone, interdialytic weight gain, blood pressures, Kt/Vs, and protein catabolic rates did not differ. We found that the change in serum bicarbonate concentration was well-tolerated and was without any demonstrable side effects. We conclude that increasing the serum bicarbonate concentration by 3 mEq/L for 16 weeks has no effect on the indicators of nutrition that we measured (serum albumin and TLC).

Vancomycin-resistant enterococcus in end-stage renal disease.

The percentage of nosocomial vancomycin-resistant enterococci (VRE) has been increasing rapidly in the United States. This has recently resulted in recommendations to reserve vancomycin use for cases with proven resistance to other antimicrobials. We prospectively investigated the incidence of VRE in our dialysis population and compared it with a control group of 40 clinic patients with chronic renal insufficiency (CRI) who had a serum creatinine level greater than 1.5 mg/dL, but were not undergoing dialysis. The incidence of VRE on our campus is almost 10%, which is similar to US data. We studied 50 chronic hemodialysis (HD) patients and 50 peritoneal dialysis (PD) patients. Each patient had a rectal swab test performed and cultured for the presence of enterococci. Antimicrobial exposures over the 6 months before the initial swab test were reviewed in each patient. At least one repeated swab test was performed in 30 CRI, 45 HD, and 37 PD patients. From the initial swab culture, vancomycin-sensitive enterococci (VSE) were isolated in 65% of CRI, 54% of HD, and 70% of PD patients. No CRI or HD patients had VRE isolated and 2% (1 of 50) of PD patients had VRE isolated. The remaining patients had no enterococci isolated. Review of antimicrobial exposures in the 6 months before the initial swab test showed 0% of CRI, 32% of HD, and 36% of PD patients received vancomycin. Other antimicrobials were administered to 40% of CRI, 46% of HD, and 78% of PD patients in the same time period. In the month immediately preceding the initial swab test, 0% of CRI, 12% of HD, and 22% of PD patients received vancomycin and 18% of CRI, 20% of HD, and 36% of PD patients received other antimicrobials. Results from repeated cultures showed that 57% of CRI, 40% of HD, and 38% of PD patients changed their culture status related to VSE, VRE, or no enterococci present. Cultures of 342 swabs from 140 patients yielded three VRE isolates in two patients. We conclude that despite the frequent use of vancomycin and other antimicrobials, the incidence of VRE in our renal population is less than the reported incidence. Given this lack of VRE isolates, we recommend the continued judicious use of vancomycin in treating renal patients and continued enterococcal sensitivity surveillance.

Neonatal endotracheal flowmeter for tidal volume, airway pressure, and end-tidal gas.

We have designed a new endotracheal flowmeter to measure tidal volume, phasic and mean airway pressures, inspiratory time, and end-tidal PCO2 and PO2 in intubated infants. The flowmeter is light (11 g) and adds minimal dead space (1.0 ml) and resistance (2 cmH2O X 100 ml- X s) to the infant's airway. The volume signal (less than or equal to 10 ml) is linear to 7 Hz, and end-tidal gases can be measured at respiratory rates of 90 breaths/min. This flowmeter is particularly valuable for evaluation of rapid mechanical ventilation of very low birth weight infants.

Conditioning of narcotic abstinence symptoms in human subjects.

Clinical evidence suggests the possibility of conditioning of narcotic abstinence symptoms. Addicts report subjective and objective signs of withdrawal/craving when exposed to certain stimuli. This may partially explain the high rate of relapse to drug seeking behavior when treated addicts return to their home environment. Conditioning of narcotic abstinence symptoms was produced experimentally in five of eight volunteer subjects. Brief naloxone precipitated abstinence was the unconditioned response. The conditioned stimulus was a tone and odor. After an average of seven training trials, the tone and odor produced a conditioned abstinence response. The conditioned response consisted of subjective components (feelings of sickness, nausea, cramps, craving) and objective components (yawning, tearing, rhinorrhea, irregular respiration and transiently increased blood pressure). These laboratory findings support the anecdotal evidence regarding the existence of conditioned abstinence phenomena.