Imaging Butyrylcholinesterase in Multiple Sclerosis.

PURPOSE: Molecular imaging agents targeting butyrylcholinesterase (BChE) have shown promise in other neurodegenerative disorders and may have utility in detecting changes to normal appearing white matter in multiple sclerosis (MS). BChE activity is present in white matter and localizes to activated microglia associated with MS lesions. The purpose of this study was to further characterize changes in the cholinergic system in MS pathology, and to explore the utility of BChE radioligands as potential diagnostic and treatment monitoring agents in MS. PROCEDURE: Cortical and white matter lesions were identified using myelin staining, and lesions were classified based on microglial activation patterns. Adjacent brain sections were used for cholinesterase histochemistry and in vitro autoradiography using phenyl 4-[123I]-iodophenylcarbamate (123I-PIP), a previously described small-molecule cholinesterase-binding radioligand. RESULTS: BChE activity is positively correlated with microglial activation in white matter MS lesions. There is no alteration in cholinesterase activity in cortical MS lesions. 123I-PIP autoradiography revealed uptake of radioactivity in normal white matter, absence of radioactivity within demyelinated MS lesions, and variable uptake of radioactivity in adjacent normal-appearing white matter. CONCLUSIONS: BChE imaging agents have the potential to detect MS lesions and subtle pathology in normal-appearing white matter in postmortem MS brain tissue. The possibility of BChE imaging agents serving to supplement current diagnostic and treatment monitoring strategies should be evaluated.

Cholinesterases in normal and Alzheimer's disease primary olfactory gyrus.

AIMS: Alzheimer's disease (AD) is characterized by cholinergic dysfunction and deposition of ß-amyloid (Aß) plaques and tau neurofibrillary tangles (NFTs) in the brain. Olfactory abnormalities often precede cognitive symptoms in AD, indicating early involvement of pathology in olfactory structures. The cholinergic system is important not only in cognition but also in modulation of the olfactory system. The primary olfactory gyrus (POG) is comprised of the olfactory tract, anterior olfactory nucleus (AON) and olfactory area (OA). Because of the importance of the olfactory and cholinergic systems, we examined the anatomical and cholinergic organization of the POG in normal human brain and neuropathology in AD. METHODS: Cytoarchitecture of the POG was studied using Nissl staining in normal (n = 8) and AD (n = 6) brains. Distributions of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were determined using histochemical methods. Aß plaques and tau NFTs were detected using immunohistochemistry. Abundance of AD pathology was assessed using a semi-quantitative approach. RESULT: Nissl staining showed pyramidal cells in the AON and paleocortical organization of the OA. AChE stained neurons and neuropil in the AON and OA, while BChE activity was noted in the olfactory tract and in AON and OA neurons. Pathology was frequent in the AD POG and the abundance of BChE-associated AD pathology was greater than that associated with AChE. CONCLUSIONS: AChE and BChE activities in normal POG recapitulated their distributions in other cortical regions. Greater abundance of BChE-associated, in comparison to AChE-associated, AD pathology in the POG suggests preferential involvement of BChE in olfactory dysfunction in AD.

The injured heart: early cardiac effects of hematopoietic stem cell transplantation in children and young adults.

We hypothesized that subclinical cardiac injury in the peri-transplant period is more frequent than currently appreciated in children and young adults. We performed echocardiographic screening on 227 consecutive patients prior to hematopoietic stem cell transplantation (HSCT), and 7, 30 and 100 days after transplant. We measured cardiac biomarkers cardiac troponin-I (cTn-I), and soluble suppressor of tumorigenicity 2 (sST2) prior to transplant, during conditioning, and days +7, +14, +28 and +49 in 26 patients. We subsequently analyzed levels of cTn-I every 48-72 h in 15 consecutive children during conditioning. Thirty-two percent (73/227) of patients had a new abnormality on echocardiogram. New left ventricular systolic dysfunction (LVSD) occurred in 6.2% of subjects and new pericardial effusion in 27.3%. Eight of 227 (3.5%) patients underwent pericardial drain placement, and 5 (2.2%) received medical therapy for clinically occult LVSD. cTn-I was elevated in 53.0% of all samples and sST2 in 38.2%. At least one sample had a detectable cTn-I in 84.6% of patients and an elevated sST2 in 76.9%. Thirteen of fifteen patients monitored frequently during condition had elevation of cTn-I. Echocardiographic and biochemical abnormalities are frequent in the peri-HSCT period. Echocardiogram does not detect all subclinical cardiac injuries that may become clinically relevant over longer periods.

Establishment and characterization of a telomerase immortalized human gingival epithelial cell line.

BACKGROUND AND OBJECTIVE: Gingival keratinocytes are used in model systems to investigate the interaction between periodontal bacteria and the epithelium in the initial stages of the periodontal disease process. Primary gingival epithelial cells (GECs) have a finite lifespan in culture before they enter senescence and cease to replicate, while epithelial cells immortalized with viral proteins can exhibit chromosomal rearrangements. The aim of this study was to generate a telomerase immortalized human gingival epithelial cell line and compare its in vitro behaviour to that of human GECs. MATERIAL AND METHODS: Human primary GECs were immortalized with a bmi1/hTERT combination to prevent cell cycle triggers of senescence and telomere shortening. The resultant cell-line, telomerase immortalized gingival keratinocytes (TIGKs), were compared to GECs for cell morphology, karyotype, growth and cytokeratin expression, and further characterized for replicative lifespan, expression of toll-like receptors and invasion by P. gingivalis. RESULTS: TIGKs showed morphologies, karyotype, proliferation rates and expression of characteristic cytokeratin proteins comparable to GECs. TIGKs underwent 36 passages without signs of senescence and expressed transcripts for toll-like receptors 1-6, 8 and 9. A subpopulation of cells underwent stratification after extended time in culture. The cytokeratin profiles of TIGK monolayers were consistent with basal cells. When allowed to stratify, cytokeratin profiles of TIGKs were consistent with suprabasal cells of the junctional epithelium. Further, TIGKs were comparable to GECs in previously reported levels and kinetics of invasion by wild-type P. gingivalis and an invasion defective ΔserB mutant. CONCLUSION: Results confirm bmi1/hTERT immortalization of primary GECs generated a robust cell line with similar characteristics to the parental cell type. TIGKs represent a valuable model system for the study of oral bacteria interactions with host gingival cells.

Venipuncture versus central venous access: a comparison of methotrexate levels in pediatric leukemia patients.

Patients receiving methotrexate (MTX) therapy for treatment of acute lymphocytic leukemia (ALL) consistently have venipuncture MTX levels drawn twice during each hospitalization. The purpose of this study was to compare MTX levels drawn from central venous catheters (CVCs) with those drawn by venipuncture. A convenience sample of 14 pediatric patients was used, with a total of 33 peak levels and 33 trough level sample pairs collected. Venipuncture and CVC levels were compared by using the paired t-test and analyzing the peak and trough data pairs separately. Results confirmed there was no difference in MTX level results (peak, p = .502; trough, p = .114). However, the CVC trough levels would have changed clinical management for 5 of the 33 patients. Therefore, it is recommended that all MTX levels be drawn from the CVC but that trough MTX levels that would alter clinical management be verified by a venipuncture sample. This method will safely minimize the number of venipunctures for children with ALL.

Effects of practice on the ability to perform lumbar stabilization exercises.

STUDY DESIGN: Randomized pretest-posttest control group design. OBJECTIVES: To determine the intratester and intertester reliability of a modified isometric stability test and to use this test to evaluate the effects of practice following a 4-week stabilization exercise program with weekly reinstruction. BACKGROUND: Although "stabilization" exercise programs are commonplace in the clinic, the reliability to a tool capable of measuring changes in the ability to perform increasingly difficult stabilization exercises has not, to our knowledge, been reported. In addition, it is not clear if practice improves the ability to perform stabilization exercises. METHODS AND MEASURES: A convenience sample of 44 asymptomatic subjects was pretested using a pressure transducer placed beneath the lumbar spine to detect motion (+/- 4 mm Hg). A series of 7 exercises was attempted, which required increasing levels of muscular control of the lumbar spine for stability. Subjects received a pass or fail for each exercise level based on the pressure gauge readings and the absence of movement compensations. Subjects were assigned randomly to exercise and nonexercise groups, and posttest measurements were taken after 4 weeks. The control group did not receive additional instruction. RESULTS: The weighted kappa coefficient of 0.61 for intratester and 0.62 for intertester represents good agreement. The median level of exercise attainment increased for the exercise group but not for the nonexercise group. CONCLUSION: These results suggest that the modified isometric stability test was reliable and that a 4-week lumbar stabilization exercise program, with weekly intervals of reinstruction and testing, improves the ability to perform progressively difficult lumbar stabilization exercises.

Effects of high-dose ipratropium bromide and oral aminophylline on spirometry and exercise tolerance in COPD.

Exercise tolerance in chronic obstructive pulmonary disease (COPD) patients treated with oral aminophylline may be different from those treated with high-dose inhaled ipratropium bromide. The purpose of this study was to compare the effects of therapeutic doses of oral aminophylline with high-dose ipratropium bromide on spirometry and exercise tolerance. The study was conducted on three consecutive days in a double-blind, randomized, crossover fashion. Baseline studies obtained on each study day included vital signs, simple spirometry and a symptom-limited maximal cardiopulmonary stress test, after which patients received one of the following treatments on each day: Treatment 1, inhaled ipratropium (total dose of 144 micrograms) with placebo tablets; Treatment 2, inhaled placebo with oral aminophylline (400 mg); Treatment 3, inhaled placebo and placebo tablets. Simple spirometry was repeated at 60 and 120 min after baseline. Vital signs and cardiopulmonary stress testing was repeated at 120 min. Eighteen patients were enrolled in the study, and 17 of these completed the study. There was a significant (P < 0.05) increase in both forced expiratory volume in 1 s (FEV1), from 0.75 (0.21) to 0.92 (0.3), and forced vital capacity (FVC), from 1.8 (0.79) to 2.11 (0.84), with high-dose ipratropium despite prior beta-agonist therapy. Lack of improvement in exercise capacity was noted with ipratropium despite improvement in spirometry. These results suggest that elderly patients with severe COPD may have exercise limitation that is not directly dependent on severity of airflow obstruction. Ipratropium bromide and aminophylline demonstrated no acute effects on exercise capacity.

Assessing juvenile sex offenders to determine adequate levels of supervision.

The present study analyzed the internal consistency of four inventories currently being used by probation officers in the state of Utah to determine adequate and efficacious supervision levels and placement for juvenile sex offenders. The internal consistency or reliability of the inventories ranged from moderate to good. Factor analysis was utilized to significantly increase the reliability of the four inventories by collapsing them into the following three factors: (a) Custodian's and Juvenile's Attitude Toward Intervention; (b) Offense Characteristics; and (c) Historical Risk Factors. These three inventories/factors explained 41.2% of the variance in the combined inventories' scores. Suggestions are made regarding the creation of an additional inventory. "Characteristics of the Victim" to account for more of the variance. In addition, suggestions as to how these inventories can be used by probation officers to make objective and consistent decisions about adequate supervision levels and placement for juvenile sex offenders are discussed.

The effect of fibrin sealant haemostasis on post-operative pain in tonsillectomy.

Pain following tonsillectomy is an important problem. It is caused by the surgical trauma of excision and haemostasis. Numerous surgical and pharmacological solutions have been tried, with disappointing results. Fibrin sealant is a widely used atraumatic haemostatic agent. This study aims to determine whether tonsillectomy with fibrin sealant haemostasis results in less post-operative pain than that with the conventional technique of diathermy. Fifty consecutive adult patients undergoing tonsillectomy were prospectively studied. They were randomized to receive either fibrin sealant or diathermy haemostasis. Other pain variables were controlled. Pain was measured by a visual linear analogue scale and inter-incisor distance on both the day of operation and the first post-operative day. The patients and pain measurer were blind to the randomization. The results showed that tonsillectomy with fibrin sealant haemostasis was significantly (P < 0.05) less painful than that with diathermy on both days studied and by both methods of pain measurement.

Nasal continuous positive airway pressure in decompensated hypercapnic respiratory failure as a complication of sleep apnea.

Cardiopulmonary failure resulting from progression of obstructive sleep apnea (OSA) is treated with endotracheal intubation and mechanical ventilation. This study was conducted to determine whether the use of nasal continuous positive airway pressure (CPAP) would rapidly reverse changes in mental status and hypercapnic acidosis in such patients with decompensated hypercapnic respiratory failure resulting from OSA. Six morbidly obese patients (mean weight, 159 +/- 19 kg) were treated with nasal CPAP and supplemental oxygen. Within 24 h of this treatment, there was a significant increase in pH, from a baseline mean of 7.23 +/- 0.03 to 7.35 +/- 0.01 (p < 0.01), and the mean PaCO2 fell from 80 +/- 4 mm Hg to 64 +/- 4 mm Hg (p < 0.01). In addition, there was a dramatic improvement in mental status within 24 h of therapy with nasal CPAP. None of the patients required intubation and mechanical ventilation. There were no complications attributable to the CPAP delivered by nasal mask. We conclude that CPAP delivered by nasal mask can be safe and effective in rapidly reversing changes in mental status and hypercapnic acidosis in this group of patients with severe respiratory failure, and nasal CPAP obviates the need for endotracheal intubation and mechanical ventilation.

Cardiopulmonary responses to continuous positive airway pressure in acute asthma.

The effects of nasal continuous positive airway pressure (CPAP) on expiratory flow, arterial blood gas tensions, cardiovascular status, and dyspnea were studied in 21 patients with acute asthma. Therapy consisted of the following CPAP sequence: 30 minutes at 5 cm H2O, 20 minutes at 0 cm H2O, 30 minutes at 7.5 cm H2O, and 20 minutes at 0 cm H2O. Six control patients were fitted with a CPAP mask but given no positive-pressure therapy. Significant reductions in respiratory rate occurred from a baseline of 22.0 +/- 1.0 to 19.8 +/- 3.8 breaths/min at CPAP 5 cm H2O and to 19.4 +/- 4.3 breaths/min at CPAP 7.5 cm H2O (P < .05). No significant change occurred in forced expiratory volume in 1 second (FEV1), heart rate, mean arterial blood pressure, or arterial blood gas tension with either level of CPAP. Dyspnea, as assessed by a breathlessness score, improved during CPAP therapy (P < .05). These levels of CPAP were tolerated without deleterious side effects. In comparison, the control group showed no change in heart rate, respiratory rate, or breathlessness score during the study period. These data show that application of CPAP in acute asthma reduces respiratory rate and dyspnea with no untoward effects on gas exchange, expiratory airflow, or hemodynamics.

Use of troleandomycin as a steroid-sparing agent in both asthma and chronic obstructive pulmonary disease.

Troleandomycin has been reported to be useful for reducing the steroid requirement of patients with asthma. The purpose of this study was to evaluate the usefulness of troleandomycin in treating patients with steroid-dependent asthma as well as in patients with steroid-dependent chronic obstructive pulmonary disease (COPD). Twelve patients with obstructive airway disease were studied; 6 patients had a diagnosis of asthma, and 6 patients had COPD. All had failed previous attempts to reduce their dosage of steroids. Among the patients with asthma, it was possible to taper methylprednisolone dosage from 29.3 +/- 21.8 mg to 11.1 +/- 7.4 11.1 mg (P less than .05). In the group with COPD there was also a significant decrease in steroid dosage--from 22.6 +/- 12.2 to 6.0 +/- 4.5 mg. These changes were not associated with a decline in spirometric values; nor was improvement secondary to improved theophylline levels, as demonstrated by a significant decrease in serum theophylline levels from 12.4 +/- 3.6 mg/dL baseline to 8.5 +/- 2.8 mg/dL (P less than .001) after maximal steroid tapering. We conclude that troleandomycin is effective in reducing the steroid dosage in patients with COPD or asthma.

Acquired tracheobronchomegaly resulting in severe respiratory failure.

Tracheobronchomegaly is a distinct clinical and radiologic entity characterized by marked dilatation of the trachea and bronchi. In this report we describe a Marfanoid patient who developed TBM in his adulthood with rapid deterioration, leading to hypercapnic respiratory failure. This case represents an acquired form of TBM in a patient with Marfanoid features which has not been previously described. Tracheobronchomegaly should be considered as a cause of chronic respiratory failure in a young adult and can be diagnosed easily with chest roentgenogram and CAT scan.

Ethanol inhibits human and hamster sperm penetration of eggs.

The effect of alcohol on the fertilizing ability of both human and hamster spermatozoa was examined by an in vitro fertilization assay using hamster ova. Spermatozoa were incubated in capacitating media for 3 hr (hamster sperm) and 4 hr (human sperm). Hamster ova were inseminated with preincubated sperm and were examined after 2 to 3 hr. Ethanol was added to the capacitating media at concentrations of 25, 50, 100, 200, and 400 mg%. Fertilization of zona-free hamster eggs by human spermatozoa was reduced from 49.6% in no alcohol to 16.7% in 400 mg% ethanol. Fertilization of hamster eggs by hamster sperm revealed a reduction from 63.6% to 33.7% in cumulus-intact eggs and from 65.8% to 10.8% in cumulus-free eggs in the presence of ethanol at 400 mg%. Hamster sperm acrosome reaction was reduced from 47% to 12%. When these hamster sperm with reduced acrosome reaction were placed with zona-free hamster eggs, the 100% fertilization rate was not reduced; however, the fertilization index, which reflects the number of swelling sperm heads per egg, was reduced from 8.5 to 1.8. This suggests that as little as 12% of the sperm with an acrosome reaction is sufficient to fertilize 100% of the zona-free eggs. If ethanol was added to the insemination media only, there was no inhibition of fertilization by human sperm or hamster sperm that had been previously capacitated in an ethanol-free media. Removal of the ethanol from the preincubated sperm produced fertilization at control levels; thus the inhibitory effect is reversible. These results indicate that ethanol may affect fertilization by an inhibition of the capacitation and/or acrosome reaction process.

Diagnosing depression in primary care: a practical, interdisciplinary review and a call for change.

Because recognizing depression is of critical importance, we have organized a comprehensive review of current literature on medical, psychiatric, and behavioral science to give primary care physicians a brief, practical, and multidisciplinary survey of diagnostic approaches to depression. The review is also designed to help clarify the disparate approaches, definitions, theories, and classifications of depression found in the literature. We emphasize two emerging perspectives important to primary care physicians in their understanding and treatment of depression. The first is a wider view of masked depression, and the second is depressive behavior related to family and cultural systems. Traditional classifications may have limited applicability to the patient families most often seen in primary care. We hope that the paper will serve as a challenge to physicians to combine open and creative observation with inductive reasoning in the creation of a more useful system for classifying depression in primary care.

Value of bronchoalveolar lavage in the diagnosis of pulmonary infection in acquired immune deficiency syndrome.

Seventy five patients with pulmonary disease and suspected acquired immune deficiency syndrome (AIDS) underwent fibreoptic bronchoscopy with bronchoalveolar lavage. Of 54 cases of Pneumocystis carinii pneumonia, 53 (98%) were diagnosed by bronchoalveolar lavage. Complications were recorded in 12 instances and included pneumothorax in two and transient increase in fever and hypoxaemia in the remainder. Bronchoalveolar lavage is a safe, easy, and effective procedure for diagnosing pneumocystis pneumonia in patients at high risk of AIDS and should be done routinely when fibreoptic bronchoscopy is performed in such patients.