Examining the limits of cellular adaptation bursting mechanisms in biologically-based excitatory networks of the hippocampus.

Determining the biological details and mechanisms that are essential for the generation of population rhythms in the mammalian brain is a challenging problem. This problem cannot be addressed either by experimental or computational studies in isolation. Here we show that computational models that are carefully linked with experiment provide insight into this problem. Using the experimental context of a whole hippocampus preparation in vitro that spontaneously expresses theta frequency (3-12 Hz) population bursts in the CA1 region, we create excitatory network models to examine whether cellular adaptation bursting mechanisms could critically contribute to the generation of this rhythm. We use biologically-based cellular models of CA1 pyramidal cells and network sizes and connectivities that correspond to the experimental context. By expanding our mean field analyses to networks with heterogeneity and non all-to-all coupling, we allow closer correspondence with experiment, and use these analyses to greatly extend the range of parameter values that are explored. We find that our model excitatory networks can produce theta frequency population bursts in a robust fashion.Thus, even though our networks are limited by not including inhibition at present, our results indicate that cellular adaptation in pyramidal cells could be an important aspect for the occurrence of theta frequency population bursting in the hippocampus. These models serve as a starting framework for the inclusion of inhibitory cells and for the consideration of additional experimental features not captured in our present network models.

Modeling oscillatory dynamics in brain microcircuits as a way to help uncover neurological disease mechanisms: a proposal.

There is an undisputed need and requirement for theoretical and computational studies in Neuroscience today. Furthermore, it is clear that oscillatory dynamical output from brain networks is representative of various behavioural states, and it is becoming clear that one could consider these outputs as measures of normal and pathological brain states. Although mathematical modeling of oscillatory dynamics in the context of neurological disease exists, it is a highly challenging endeavour because of the many levels of organization in the nervous system. This challenge is coupled with the increasing knowledge of cellular specificity and network dysfunction that is associated with disease. Recently, whole hippocampus in vitro preparations from control animals have been shown to spontaneously express oscillatory activities. In addition, when using preparations derived from animal models of disease, these activities show particular alterations. These preparations present an opportunity to address challenges involved with using models to gain insight because of easier access to simultaneous cellular and network measurements, and pharmacological modulations. We propose that by developing and using models with direct links to experiment at multiple levels, which at least include cellular and microcircuit, a cycling can be set up and used to help us determine critical mechanisms underlying neurological disease. We illustrate our proposal using our previously developed inhibitory network models in the context of these whole hippocampus preparations and show the importance of having direct links at multiple levels.

Shift in sleep apnoea type in heart failure patients in the CANPAP trial.

In patients with heart failure (HF), the predominant type of sleep apnoea can change over time in association with alterations in circulation time. The aim of this study was to determine whether, in some patients with HF, a spontaneous shift from mainly central (>50% central events) to mainly obstructive (>50% obstructive events) sleep apnoea (CSA and OSA, respectively) over time coincides with improvement in left ventricular ejection fraction (LVEF). Therefore, sleep studies and LVEFs of HF patients with CSA from the control arm of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure (CANPAP) trial were examined to determine whether some converted to mainly OSA and, if so, whether this was associated with an increase in LVEF. Of 98 patients with follow-up sleep studies and LVEFs, 18 converted spontaneously to predominantly OSA. Compared with those in the nonconversion group, those in the conversion group had a significantly greater increase in the LVEF (2.8% versus -0.07%) and a significantly greater fall in the lung-to-ear circulation time (-7.6 s versus 0.6 s). In patients with HF, spontaneous conversion from predominantly CSA to OSA is associated with an improvement in left ventricular systolic function. Future studies will be necessary to further examine this relationship.

Effects of different dietary fats on mammary carcinogenesis.

Mammary tumor induction was examined in female Fischer rats fed a low-corn oil, a high-corn oil, a high-lard, a high-beef tallow, or a high-coconut oil diet since weaning. The diets were prepared by adding the experimental fat to a basal diet containing sufficient essential fatty acids for growth. These diets differed only in the concentration or type of dietary fat. The rats were given a single i.v. dose (50 mg/kg body weight) of N-nitrosomethylurea at 50 days of age. Mammary tumor incidences 28 weeks after N-nitrosomethylurea treatment in rats on low-corn oil, high-corn oil, high-lard, high-beef tallow, and high-coconut oil diets were 33, 85, 65, 50, and 43%, respectively. The data show that an increase in fat intake enhances mammary carcinogenesis, but the magnitude of the increase depends on the type of fat. Further analyses showed that the total oleic and linoleic acid intake in the five groups of rats correlated positively (r = 0.95) with mammary tumor incidence, whereas the composition of the mammary tissue neutral lipids and phospholipids did not. Our data suggest that the total oleate and linoleate intake in the high-fat diet is the major factor influencing the incidence of tumors by N-nitrosomethylurea.

A cytochrome b5 electron transport chain in Tetrahymena.

Tetrahymena microsomes contain cytochrome b5 and an NADH-dependent cytochrome b5 reductase, but these proteins are present at only one-tenth the levels observed in rat liver microsomes. We show that both proteins can be partially purified by techniques developed for the rat liver proteins. We can show that cyanide inhibits the rate of exhaustion of NADH, and therefore reoxidation of cytochrome b5 by microsomes, and that stearoyl CoA enhances the rate of reoxidation of the cytochrome. Also, we find that a fragment of rat liver NADH-cytochrome b5 reductase can restore NADH-dependent cytochrome b5 reduction to Tetrahymena microsomes which have been treated with N-ethylmaleimide to eliminate endogenous reductase activity. These results indicate that there is considerable resemblance between the rat and Tetrahymena systems, and that desaturation of stearoyl and oleoyl groups may occur in Tetrahymena via pathways similar to those known in liver.

Oleic acid desaturation in Tetrahymena pyriformis.

The desaturation of oleoyl-CoA by a microsomal preparation from Tetrahymena has been studied. Desaturation of oleoyl-CoA required oxygen and NADH, and was inhibited by cyanide. HPLC analysis of fatty acid phenacyl esters, prepared from TLC-purified phospholipid, confirmed that radioactivity appeared in oleate, linoleate and gamma-linolenate. Both the time course of desaturation and the apparent desaturation of 1-palmitoyl-2-[14C]oleoylphosphatidylcholine suggested that phospholipid-bound oleate could be a substrate for desaturation. In the crude microsomal preparation, acylation of oleoyl-CoA to give oleoyl phospholipid was rapid. Therefore, preincubation in the absence of NADH was employed to create [14C]oleoyl phospholipids, and kinetic studies were carried out upon subsequent addition of NADH. When data were plotted in a double reciprocal form, a linear function was observed.

Differential biosynthesis of polyunsaturated fatty acids by Tetrahymena supplemented with ergosterol.

Tetrahymena grown with foreign sterols such as ergosterol incorporate them into cellular membranes at the expense of the native compound, tetrahymanol. It is shown that cells grown with ergosterol have a lessened capacity to produce the polyunsaturated linoleic and gamma-linolenic acids from [14C]oleic acid. However, the same cells have normal capacities to introduce double bonds at C-6 into linoleate, alpha-linolenate, or cis-vaccenate. Thus, a presumed 12-desaturase is inhibited in the presence of ergosterol, while desaturation at C-6 is unaffected.

Phase behavior of the major lipids of tetrahymena ciliary membranes.

The major lipids of Tetrahymena membranes have been purified by thin-layer and high pressure liquid chromatography and the phosphatidylethanolamine and aminoethylphosphonate lipids were examined in detail. 31P-NMR, X-ray diffraction and freeze-fracture electron microscopy were employed to describe the phase behavior of these lipids. The phosphatidylethanolamine was found to form a hexagonal phase above 10 degrees C. The aminoethylphosphonate formed a lamellar phase up to 20 degrees C, but converted to a hexagonal phase structure at 40 degrees C. Small amounts of phosphatidylcholine stabilized the lamellar phase for the aminoethylphosphonate. 31P-NMR spectra of the intact ciliary membranes were consistent with a phospholipid bilayer at 30 degrees C, suggesting that phosphatidylcholine in the membrane stabilized the lamellar form, even though most of the lipid of that membrane prefers a hexagonal phase in pure form at 30 degrees C. 31P-NMR spectra also showed a distinctive difference in the chemical shift tensor of the aminoethylphosphonolipid, when compared to that of phosphatidylethanolamine, due to the difference in chemical structure of the polar headgroups of the two lipids.

Oral appliance therapy for the treatment of obstructive sleep apnea.

A variety of oral appliances (OA) are now available for the treatment of obstructive sleep apnea (OSA), OA therapy is effective in some patients with mild to moderate OSA and is associated with greater patient satisfaction than nasal CPAP. Adjustable OA are associated with improved treatment success and fewer compliance failures compared to non-adjustable OA. Large randomized clinical trials are necessary to further determine the precise indications, benefits, and risks of each OA in the treatment of OSA.

Treatment, airway and compliance effects of a titratable oral appliance.

STUDY OBJECTIVES: To measure the effects of a titratable anterior mandibular repositioner on airway size and Obstructive Sleep Apnea (OSA) and to evaluate its compliance. DESIGN: Before and after insertion sleep studies were obtained in a total of 38 OSA patients of varying severity from three different sites. Covert compliance was measured by means of a newly-developed, miniaturized, temperature-sensitive, imbedded monitor. Validity testing was completed in six adult volunteers who wore monitors imbedded into small acrylic appliances. MEASUREMENTS AND RESULTS: The mean RDI before treatment was 32.6 (SEM 2.1) and after the insertion of the appliance, the RDI was reduced to 12.1 (SEM 1.7, p<0.001). RDI was reduced to less than 15/hour in 80% of a group of moderate OSA patients (RDI 15 to 30) and in 61% of a group of severe OSA patients (RDI > 30) with respect to baseline RDI. Fiber optic video endoscopy was performed on 9 OSA patients with and without the appliance. No significant differences in hypopharynx or oropharynx cross sectional areas were found, but at the level of the velopharynx, the airway size was significantly increased (p<0.05). The index of agreement was 0.99 between the monitor clock time and the subject's log sheets. Compliance data from eight OSA subjects instructed to wear the appliance during sleep indicated that it was worn for a mean of 6.8 hours with a range of 5.6 to 7.5 hours per night. CONCLUSION: The titratable adjustable mandibular advancement appliance, made from thermoelastic acrylic, significantly reduces RDI in moderate to severe OSA patients, has a direct effect on airway size and is well worn throughout the night.

Sleep-disordered breathing in amyotrophic lateral sclerosis.

OBJECTIVE: The purpose of this study was to assess sleep and breathing in patients with amyotrophic lateral sclerosis (ALS) with bulbar muscle involvement. DESIGN: Prospective, controlled study of sleep and breathing measured during polysomnography. SETTING: University teaching hospital and referral center. PATIENTS: Patients with definite ALS and healthy age-matched control subjects. INTERVENTIONS: Eighteen ALS patients and 10 age-matched control subjects underwent one night of polysomnography. Thirteen patients with ALS were studied for a second night. RESULTS: The ALS patients had more arousals per hour (p = 0.008), more stage 1 sleep (p = 0.01), and a shorter total sleep time (TST) (279 +/- 69 vs 331.4 +/- 55.9 min, mean +/- SD, p = 0.04) than the control subjects. The ALS patients had mild sleep-disordered breathing with a greater apnea/hypopnea index (AHI) than the control subjects (p = 0.005). On the second night of polysomnography, there was an increase in TST (p = 0.003) and rapid eye movement (REM) sleep (p = 0.009), an improvement in sleep efficiency (p = 0.02), and less stage 1 sleep (p = 0.04). Eight ALS patients had sleep-disordered breathing consisting of periods of hypoventilation, predominantly during REM sleep. CONCLUSIONS: Sleep-disordered breathing occurs in patients with ALS and is similar to patients without ALS with respiratory muscle weakness. No obstructive sleep apnea was observed. One potential reason for its absence might be the inability of patients with respiratory muscle weakness to generate an inspiratory pressure greater than the upper airway closing pressure. This hypothesis should be addressed in future studies.

The relationship between obesity and craniofacial structure in obstructive sleep apnea.

STUDY OBJECTIVE: To evaluate the interaction between craniofacial structure and obesity in male patients with obstructive sleep apnea (OSA). DESIGN: Retrospective analysis of a cohort of OSA patients. The relationships between neck circumference (NC), body mass index, apnea severity, and craniofacial and upper airway soft-tissue measurements from upright lateral cephalometry were examined. Patients were divided into groups; small to normal NC (group A), intermediate NC (group B), or large NC (group C). SETTING: A university teaching hospital and tertiary sleep referral center. PATIENTS: A consecutive series of patients with OSA who underwent polysomnography and lateral cephalometry. MEASUREMENTS AND RESULTS: Group A patients were less obese and had more craniofacial abnormalities such as a smaller mandible and maxilla and a more retrognathic mandible. Group B patients had both upper airway soft-tissue and craniofacial abnormalities. Group C patients were more obese with larger tongues and soft palates, and an inferiorly placed hyoid. Group C patients also had fewer craniofacial abnormalities than group A or B patients. There was no difference in airway size among the three groups. CONCLUSIONS: We conclude that there is a spectrum of upper airway soft-tissue and craniofacial abnormalities among OSA patients: obese patients with increased upper airway soft-tissue structures, nonobese patients with abnormal craniofacial structure, and an intermediate group of patients with abnormalities in both craniofacial structure and upper airway soft-tissue structures.

A randomized crossover study of an oral appliance vs nasal-continuous positive airway pressure in the treatment of mild-moderate obstructive sleep apnea.

STUDY OBJECTIVE: To compare efficacy, side effects, patient compliance, and preference between oral appliance (OA) therapy and nasal-continuous positive airway pressure (N-CPAP) therapy. DESIGN: Randomized, prospective, crossover study. SETTING: University hospital and tertiary sleep referral center. PATIENTS: Twenty-seven unselected patients with mild-moderate obstructive sleep apnea (OSA). INTERVENTIONS: There was a 2-week wash-in and a 2-week wash-out period, and 2 x 4-month treatment periods (OA and N-CPAP). Efficacy, side effects, compliance, and preference were evaluated by a questionnaire and home sleep monitoring. MEASUREMENTS AND RESULTS: Two patients dropped out early in the study and treatment results are presented on the remaining 25 patients. The apnea/hypopnea index was lower with N-CPAP (3.5 +/- 1.6) (mean +/- SD) than with the OA (9.7 +/- 7.3) (p < 0.05). Twelve of the 25 patients who used the OA (48%) were treatment successes (reduction of apnea/hypopnea to <10/h and relief of symptoms), 6 (24%) were compliance failures (unable or unwilling to use the treatment), and 7 (28%) were treatment failures (failure to reduce apnea/hypopnea index to <10/h and/or failure to relieve symptoms). Four people refused to use N-CPAP after using the OA. Thirteen of the 21 patients who used N-CPAP were overall treatment successes (62%), 8 were compliance failures (38%), and there were no treatment failures. Side effects were more common and the patients were less satisfied with N-CPAP (p < 0.005). Seven patients were treatment successes with both treatments, six of these patients preferred OA, and one preferred N-CPAP as a long-term treatment. CONCLUSIONS: We conclude that OA is an effective treatment in some patients with mild-moderate OSA and is associated with fewer side effects and greater patient satisfaction than N-CPAP.

Neural network prediction of obstructive sleep apnea from clinical criteria.

STUDY OBJECTIVES: Clinical prediction models for the diagnosis of obstructive sleep apnea (OSA) have lacked the accuracy necessary to confidently replace polysomnography (PSG). Artificial neural networks are computer programs that can be trained to predict outcomes based on experience. This study was conducted to test the hypothesis that a generalized regression neural network (GRNN) could accurately classify patients with OSA from clinical data. STUDY DESIGN: Retrospective review. SETTING: Regional sleep referral center. PATIENTS: Randomly selected records of patients referred for possible OSA. MEASUREMENTS: The neural network was trained using 23 clinical variables from 255 patients, and the predictive performance was evaluated using 150 other patients. RESULTS: The prevalence of OSA in this series of 405 patients (293 men and 112 women) was 69%. The trained GRNN had an accuracy of 91.3% (95% confidence interval [CI], 86.8 to 95.8). The sensitivity was 98.9% for having OSA (95% CI, 96.7 to 100), and the specificity was 80% (95% CI, 70 to 90). The positive predictive value that the patient would have OSA was 88.1% (95% CI, 81.8 to 94.4), whereas the negative predictive value that the patient would not have OSA (if so classified) was 98% (95% CI, 94 to 100). CONCLUSIONS: Appropriately trained GRNN has the ability to accurately rule in OSA from clinical data, and GRNN did not misclassify patients with moderate to severe OSA. In this study, use of the neural network could have reduced the number of PSG studies performed. Prospective validation of the neural network for the diagnosis of OSA is now required.

Chromosomal abnormalities associated with infertility.

From a population of 515 subfertile couples and 119 women with amenorrhea, 38 patients were karyotyped because of specific signs and symptoms suggestive of chromosomal abnormality. The indications for karyotyping included primary amenorrhea, secondary amenorrhea with gonadal failure before 35 years of age, stature of less than 147.5 cm, azoospermia with eunuchoidism, and personal or family history of more than 2 spontaneous abortions or more than 2 severely abnormal children. In addition, 19 patients from the same subfertile population were selected randomly for karyotyping to serve as controls. Using banding techniques, chromosomal abnormalities were found in 18 of the 38 specifically selected individuals, whereas no abnormality was found among those randomly selected. Three of the 18 patients had chromosomal abnormalities not previously described; their karyotypes were 46,XY/48,XY,+8,+21; 46,X,inv dup(Xq)/q26 leads to q21); and 46,XY,t(9;20)(q22;q12).

Outpatient abortion for fetal anomaly and fetal death from 15-34 menstrual weeks' gestation: techniques and clinical management.

OBJECTIVE: To determine the safety of providing outpatient abortion services for women with complicated advanced pregnancies. METHODS: During a 10-year period, 124 abortions were performed after 14 menstrual weeks' gestation at an outpatient abortion facility for indications of fetal anomaly, diagnosed genetic disorder, or fetal death. Gestational lengths ranged from 15-34 menstrual weeks. Fetal diagnoses included a variety of chromosomal abnormalities, malformations, and death. Techniques for performing the late abortions included a serial multiple laminaria method of cervical dilation. Abortions performed after 20 menstrual weeks were effected by instillation of intra-amniotic hyperosmolar urea or induction of fetal death by injection of digoxin and/or hyperosmolar urea into the fetus, followed by artificial rupture of membranes, induction of labor, and assisted expulsion or instrumental extraction of the fetus. At less than 20 weeks, dilation and evacuation following serial multiple laminaria treatment of the cervix was the method of choice. RESULTS: The median gestational age was 23 menstrual weeks. The median procedure time for all cases was 12 minutes and median blood loss was 125 mL. Procedure time increased with length of gestation (P = .00). Blood loss was only slightly increased by gestation length (P = .154) and not by procedure time (P = .299). Complication rates were not significantly related to gestation length (P = .895). There was one major complication in this series. There were no uterine perforations and one cervical laceration. CONCLUSION: Outpatient abortion may be performed safely in most cases of fetal disorder, including death, through 34 menstrual weeks under proper conditions.

Interinstitutional study to compare the effectiveness of a radiology-anatomy module of instruction.

RATIONALE AND OBJECTIVES: The purpose of this study was to validate the effectiveness of a proven radiology-anatomy instructional module during I st-year gross anatomy courses at Emory University College of Medicine and the University of Iowa College of Medicine. MATERIALS AND METHODS: This prospective study involved 108 Emory students and 177 Iowa students. The instructional content was the same at both institutions. Each student was randomly assigned into one of three groups at each institution, and each group received a unique, randomized, five-item pretest. All students were posttested as part of their gross anatomy laboratory examination, and the posttests consisted of all 15 items used in the three five-item pretests. RESULTS: No statistically significant pretest effects were demonstrated by t tests. Posttest performances across items ranged from 73% to 96% correct for Emory students and 67% to 98% for Iowa students. Performance levels on the posttests were significantly higher than on pretests, and few significant differences were found in the performance of the two populations. CONCLUSION: The radiology-anatomy instructional module integrated into the gross anatomy courses for 1st-year Emory University and University of Iowa students was not instructor or institution dependent.

A protocol for the initial management of unstable pelvic fractures.

The initial management of life-threatening hemorrhage associated with severe pelvic fractures has long been a source of debate. A review of the literature reveals that many advocate emergent orthopedic external fixation (EX-FIX) for severe pelvic fractures, whereas others claim greater success with angiographic embolization (ANGIO) as the first line of treatment. Although many have attempted to classify management options by fracture pattern, to date there has been no prospective trial comparing outcomes for each method of treatment. We offer a prospective study of all pelvic fracture patients admitted to our Level I trauma center between July 1994 and July 1995. Patients were classified according to fracture pattern and degree of hemodynamic instability. Those with primarily anterior pelvic ring fractures underwent emergent EX-FIX for control of hemorrhage, whereas those with primarily posterior pelvic ring fractures underwent emergent ANGIO to control hemorrhage. We found that blood product requirements and hospital stay were similar in each group. However, the complication rate was higher in patients who underwent initial emergency EX-FIX, primarily because of failure to adequately control hemorrhage. We conclude that patients with anterior-posterior compression type 2 and 3, lateral compression type 2 and 3, or vertical shear injuries, who are hemodynamically unstable as a result of their pelvic fracture, should undergo immediate ANGIO if laparotomy is not indicated. If laparotomy is indicated, EX-FIX should be placed intraoperatively, followed by postoperative ANGIO.

Fatty acid desaturase specificity of Tetrahymena.

The ciliate, Tetrahymena, was provided a supplement of the fatty acid [1-14 C]18:2 delta 6.9. After a period of growth the cells were claimed, the lipids extracted, the polar lipids recovered and the mild alkali-labile fatty acid methyl esters generated. The fatty acids were resolved by high pressure liquid chromatography (HPLC), the 18:3 delta 6.9,12(gamma-linolenic acid) was recovered and its identity verified by high pressure liquid chromatography (HPLC), gas liquid chromatography (GLC), hydrogenation and oxidation. Fifty-three percent of the cell-associated label was found in gamma-linolenic acid; thus, a delta 12 fatty acid desaturase converts the 6,9 octadecadienoic acid to the 6,9,12 derivative. No carboxyl or methyl terminus restriction appears on delta 9 monoenoic or dienoic fatty acid desaturation in this cell as is found in higher plants and animals.

Amiodarone pulmonary, neuromuscular and ophthalmological toxicity.

Amiodarone is an iodinated benzofuran derivative class III antiarrhythmic that is highly effective in suppressing ventricular and supraventricular arrhythmias. It is also associated with an imposing side effect profile, which often limits its use. Numerous adverse effects have been documented including skin discolouration, photosensitivity, hepatitis, thyroid dysfunction, corneal deposits, pulmonary fibrosis, bone marrow suppression and drug interactions. These side effects are thought to be correlated with the total cumulative dose of amiodarone, but idiopathic reactions have been reported. The majority of adverse reactions resolve with discontinuation of the drug; however, rapid progression may occur, which may be fatal. The present report documents a patient who had a combination of serious amiodarone toxicities that, once recognized, were treated and eventually resulted in a good outcome.