A non-circadian role for cAMP signaling and CREB activity in Drosophila rest homeostasis.

In the fruit fly, Drosophila melanogaster, rest shares features with mammalian sleep, including prolonged immobility, decreased sensory responsiveness and a homeostatic rebound after deprivation. To understand the molecular regulation of sleep-like rest, we investigated the involvement of a candidate gene, cAMP response-element binding protein (CREB). The duration of rest was inversely related to cAMP signaling and CREB activity. Acutely blocking CREB activity in transgenic flies did not affect the clock, but increased rest rebound. CREB mutants also had a prolonged and increased homeostatic rebound. In wild types, in vivo CREB activity increased after rest deprivation and remained elevated for a 72-hour recovery period. These data indicate that cAMP signaling has a non-circadian role in waking and rest homeostasis in Drosophila.

The effects of ondansetron on sleep-disordered breathing in the English bulldog.

Serotonin and serotoninergic drugs have significant effects on respiration, at many sites throughout the nervous system, and serotonin has been implicated in the pathogenesis of obstructive sleep apnea. Thus, understanding the serotoninergic mechanisms underlying respiratory control may help discover novel pharmacotherapies for sleep-disordered breathing. Ondansetron, a serotonin (5-HT) antagonist selective for the 5-HT3 receptor subtype has recently been shown to suppress sleep-related central apneas in rats, particularly in rapid-eye-movement (REM) sleep. To evaluate the potential of ondansetron in the treatment of obstructive sleep-disordered breathing, we have performed randomized trials of two doses of ondansetron (20 and 40 mg orally) and placebo (4 studies for each of the 3 conditions) in our animal model of obstructive sleep apnea, the English Bulldog. Ondansetron significantly reduced the respiratory disturbance index (RDI) in REM sleep from 24.15+/-4.85 events/hour at placebo to 11.01+/-1.56 events/hour with high dose treatment, n=4, p<0.05. In contrast, the effects of drug on the RDI in non-rapid-eye-movement (NREM) sleep (5.23+/-1.30 events/hour, placebo; 4.31+/-1.36, with 20 mg ondansetron and 2.89+/-1.30 with 40 mg ondansetron, n=4) were not significant. Ondansetron, however, had no effect on either sleep efficiency or sleep architecture, and there were no effects on either oxyhemoglobin saturation nadirs or on the sleep time with saturations <90%. Although a trend towards reduction in the latter measure of oxygenation was seen at the higher dose of ondansetron. These data suggest a therapeutic potential for ondansetron in obstructive sleep-disordered breathing, particularly REM sleep apnea.

Rest in Drosophila is a sleep-like state.

To facilitate the genetic study of sleep, we documented that rest behavior in Drosophila melanogaster is a sleep-like state. The animals choose a preferred location, become immobile for periods of up to 157 min at a particular time in the circadian day, and are relatively unresponsive to sensory stimuli. Rest is affected by both homeostatic and circadian influences: when rest is prevented, the flies increasingly tend to rest despite stimulation and then exhibit a rest rebound. Drugs acting on a mammalian adenosine receptor alter rest as they do sleep, suggesting conserved neural mechanisms. Finally, normal homeostatic regulation depends on the timeless but not the period central clock gene. Understanding the molecular features of Drosophila rest should shed new light on the mechanisms and function of sleep.

The need for a simple animal model to understand sleep.

Simple animal models have allowed biologists to apply the tools of modern molecular genetics to such complex behaviors as circadian rhythms and long-term memory consolidation. The mechanisms and molecules discovered in these simple animals are evolutionarily conserved in other species, including mammals. Sleep research lacks a simple animal model because criteria based on the electroencephalogram have been met only in birds and mammals. We argue that straightforward behavioral criteria could allow the identification of a sleep-like rest state that might be useful for molecular investigations to understand the regulation and function of sleep. Candidate model systems are discussed, leading to the conclusion that several species have complementary strengths. Specifically, techniques developed for larval zebrafish can be used to visualize neural firing patterns in the living animal, and the fruit fly Drosophila melanogaster has been used successfully for molecular and genetic dissection of complex behaviors. We conclude with a hypothesis that one putative function of sleep, the optimization of neural plasticity, would also have adaptive value in simple organisms and might therefore be evolutionarily conserved.

Smoke exposure in cats: 22 cases (1986-1997).

OBJECTIVE: To review clinical findings and clinical course for cats exposed to smoke in residential fires and to determine clinical variables that may have prognostic importance. DESIGN: Retrospective study. ANIMALS: 22 cats admitted to our veterinary teaching hospital between 1986 and 1997 with a history of smoke exposure during a residential fire. PROCEDURE: Medical records were reviewed for history, clinical signs, physical examination findings, changes in respiratory tract signs, initial hematologic analysis, treatment, results of thoracic radiography, and outcome. RESULTS: Fifteen of 22 (68%) cats were categorized in the uncomplicated group, 5 (23%) in the complicated group, and 2 (9%) were discharged after a short period because of financial considerations. Twenty (91%) cats survived, but 2 (9%) were euthanatized because of severe respiratory compromise or neurologic changes. Predominant thoracic radiographic changes were diffuse interstitial pattern (6 cats) and focal alveolar pattern (5). The majority (8/13) of cats that were stable or had improved by the day after admission had an uncomplicated clinical course while hospitalized, whereas cats that were worse on the day after admission tended to have a complicated clinical course. CONCLUSIONS AND CLINICAL RELEVANCE: Cats that survive a residential fire and are admitted to a hospital have a good chance to be discharged. Cats that do not have signs of respiratory tract dysfunction at admission probably will not develop severe respiratory complications. For cats with signs of respiratory dysfunction at admission, better prognostic information will be determined by monitoring progression of the respiratory condition on the day after admission.

Smoke exposure in dogs: 27 cases (1988-1997).

OBJECTIVE: To evaluate clinical findings, prognostic variables, and clinical course of dogs exposed to smoke. DESIGN: Retrospective study. ANIMALS: 27 dogs exposed to smoke in residential fires. PROCEDURE: Medical records were reviewed for 1988-1997. Time of year, signalment, interval from fire to arrival at veterinary hospital, duration of smoke exposure, clinical signs at the fire scene, physical examination findings, changes in respiratory tract signs, radiographic findings, hematologic and arterial blood gas analyses, initial treatment, clinical course, and outcome were recorded. RESULTS: 27 dogs (16 uncomplicated and 11 complicated cases) were identified. In the complicated group, 4 dogs died, 4 were euthanatized, and 3 had a complicated clinical course. Stupor or coma (8 of 17 dogs), coughing or gagging (6), and respiratory difficulty (6) were commonly observed at the fire scene. Substantial improvement was evident within 5 to 30 minutes after dogs were given supplemental oxygen at the fire scene. More severely affected dogs had a higher median PCV (58%) than less severely affected dogs (50%). Most common thoracic radiographic findings were an alveolar (10 dogs) or an interstitial (3) pattern. CONCLUSIONS AND CLINICAL RELEVANCE: Dogs exposed to smoke can develop respiratory or neurologic complications. Monitoring progression of respiratory problems on the day after the fire may provide clinicians with clues about the severity of each dog's condition.

The effects of trazodone with L-tryptophan on sleep-disordered breathing in the English bulldog.

Obstructive sleep apnea hypopnea syndrome (OSAHS) is a prevalent disorder, for which there are no universally effective pharmacotherapeutics. We hypothesized that in OSAHS, excitatory serotoninergic influences are important for maintaining patency of the upper airway in waking, and that in sleep, reduced serotoninergic drive plays a significant role in upper airway collapse and OSAHS. The previously reported small responses in humans with OSAHS to serotoninergics may relate, in part, to study design and the drugs/doses selected. We therefore performed multitrials/dose, multidose, randomized sleep studies testing the effectiveness of a combination of serotoninergics, trazodone, and L-tryptophan, in our animal model of OSAHS, the English bulldog. Trazodone/L-tryptophan caused dose-dependent reductions in respiratory events in non-rapid-eye-movement sleep (NREMS) and rapid-eye-movement sleep (REMS). During NREMS, the respiratory disturbance index (RDI) +/- standard error was 6.3 +/- 1.4 events/h (placebo) and 0.9 +/- 0.3 (highest dose), p < 0.01. During REMS, the RDI was 31.4 +/- 6.1 events/h (placebo) and 11.5 +/- 4.3 (highest dose), p = 0.002. Trazodone/ L-tryptophan dose-dependently reduced sleep fragmentation, p = 0.03, increased sleep efficiency, p = 0.005, enhanced slow-wave sleep, p = 0.0004, and minimized sleep-related suppression of upper airway dilator activity, p < 0.02. Trazodone with L-tryptophan can treat sleep-disordered breathing (SDB) in an animal model of OSAHS; the effectiveness of this therapy may be related to increased upper airway dilator activity in sleep and/or enhanced slow-wave sleep.

Quantification of cerebral ventricular volume in English bulldogs.

Quantitative measurement of cerebral ventricle volume of eight English bulldogs was performed using magnetic resonance (MR) imaging. The mean ventricular volume was 14.8 ml. with a range of 8.6 ml.-38.1 ml. The mean ventricular volume of two beagles was 2.2 ml with a range of 0.7 ml.-3.7 ml. The percent of intracranial volume occupied by ventricle was found to be significantly larger in bulldogs (14.0%; S.D. = 7.9%) than in beagles (Range = 1.0-4.8%). The relationship between the percent of intracranial volume occupied by ventricle and measurements of body weight, age, sex, and various measures of skull anatomy of the bulldog was also determined. The relationship between ventricular volume and neurologic dysfunction was examined. There was a possible trend between high percent of intracranial volume occupied by ventricle and low body weight. This study will serve as a pilot study for examining the relationship between ventricular volume and neurologic disease in bulldogs.

Open versus stereotactic breast biopsy.

BACKGROUND: Stereotactic breast biopsy has been developed as a less invasive means of performing biopsy for mammographic abnormalities. METHODS: From July 1994 through June 1995, 103 women with mammographic abnormalities requiring biopsy were prospectively evaluated. RESULTS: Fifty-one women had open biopsy, and 52 women had stereotactic biopsy. The average age in both groups was 60 years. Pathology revealed malignancy in 12% of stereotactic biopsies and 13% of open biopsies. Complications occurred in 6% of the open biopsies and 4% of the stereotactic biopsies and were limited to hematomas or seromas. The average cost was $2400 for open biopsy and $650 for stereotactic biopsy (P < 0.01). One hundred and one patients returned for a follow-up mammogram within 6 months, and 1 patient in each group required a second biopsy, which revealed benign pathology. A Patient Satisfaction Survey revealed no significant differences in patient satisfaction between the two types of procedures. CONCLUSION: There were no differences between open and stereotactic biopsies in regards to diagnostic accuracy, complications, or patient satisfaction. A significant difference was noted in charges during the time frame of our study.

Modafinil decreases hypersomnolence in the English bulldog, a natural animal model of sleep-disordered breathing.

The English bulldog is a natural model of sleep-disordered breathing (SDB). This condition is marked by 1) hypersomnolence and 2) disordered breathing episodes that are most frequent and severe during rapid eye movement (REM) sleep. Modafinil has been found to increase arousal levels in animals and decrease excessive daytime sleepiness in humans. Therefore, in this study we focused mainly on the effects of the drug on total sleep time and sleep latency and secondarily assessed its effect on REM SDB. Five English bulldogs were implanted with subcutaneous electroencephalographic/electrooculographic (EEG/EOG) electrodes and instrumented with respiratory oscillation belts to measure abdominal and rib cage movements and an ear oximeter to measure saturation. The dogs were studied for approximately 8 hours each subsequent day on two consecutive days. On the first day, they received the vehicle dimethyl sulfoxide (DMSO) i.v. as a control. On the following day they received 10 mg/kg body weight of modafinil i.v. dissolved in the DMSO vehicle. Our findings indicate that modafinil significantly alleviates hypersomnolence (p < 0.05) in the bulldog, as evidenced by dramatically decreased mean total sleep time (from a control value of 50.5% to 8.3% with the drug) and increased mean sleep latency (from a control value of 71.0 minutes to a value of 346.6 minutes with the drug). We obtained limited data on the effect of modafinil on SDB because the drug either greatly diminished or entirely eradicated REM sleep in all five dogs.

Quantitative magnetic resonance imaging of upper airways musculature in an animal model of sleep apnea.

Electromyographic studies of patients with sleep apnea and of the English bulldog, an animal model of sleep apnea, indicate that there is increase activity of the airways dilator muscles. The muscles, when biopsied, show both adaptation and muscle injury. In this study we have utilized quantitative magnetic resonance imaging to characterize changes in the upper airway musculature of the bulldog in vivo. The imaging procedure utilized provided a quantitative measurement of the T2 relaxation times of airway muscle (geniohyoid, sternohyoid, sternothyroid, thyropharyngeus, and hyopharyngeus) and nonairway muscles spatially localized to submillimeter-resolution levels. Quantitative differences between the medians and distributions of T2 relaxation times of airway vs. nonairway muscles were demonstrated. These differences were related to the degree of sleep-disordered breathing. The changes observed are compatible with the hypothesis that there is both increased edema and fibrosis in upper airway muscle in sleep apnea.

Does upper airway muscle injury trigger a vicious cycle in obstructive sleep apnea? A hypothesis.

Recent studies have indicated that the level of neural activation of upper airway dilator muscles is abnormally elevated in patients with obstructive sleep apnea (OSA). This is presumed to represent an adaptive mechanism that partially compensates for the anatomically small upper airway found in individuals with OSA. We have reviewed evidence that pharyngeal dilator muscles undergo secondary changes in structure as a direct consequence of their increased activity level in OSA. These alterations have the potential to be both beneficial and harmful with respect to the maintenance of upper airway patency. We propose a model outlining the possible role of activity-induced upper airway muscle remodeling and injury in the pathogenesis of OSA, and discuss potential implications for treatment of the disease.

The effects of serotonin antagonists in an animal model of sleep-disordered breathing.

Recent studies have shown excitatory effects of serotonin on upper airway motoneurons. This excitatory effect is normally present and arises from cells in the caudal raphe nuclei. The firing of these serotonergic neurons is reduced during sleep. To determine the importance of serotonin in the maintenance of patient airways and normal respiration in waking in obstructive sleep apnea, we studied the effects of two serotonin antagonists on upper airway dilator muscle activity, diaphragm activity, Sao2, and upper airway cross-sectional area in an animal model of sleep-disordered breathing, the English bulldog. Systemic administration of both antagonists resulted in significant reductions in the peak amplitudes of upper airway muscle respiratory bursts (range, 39 to 62% suppression; p < 0.05). Lesser reductions in diaphragm activity were noted (range, 10 to 33% suppression; p < 0.05). Oxyhemoglobin saturations also fell (p < 0.05), coinciding with suppressions in upper airway muscle activity. With reductions in dilator muscle activity, upper airway cross-sectional areas, as measured with cine CT, showed significant inspiratory collapse. These results support the hypothesis that serotonin is important in the maintenance of patent upper airways in obstructive sleep apnea.

Transanal excision of rectal carcinoma.

Twenty-two men and 16 women with a mean age of 67 years were treated for rectal carcinoma by transanal excision. Patients presented with rectal bleeding (63%), change in bowel habits (11%), rectal pain (4%), or were asymptomatic and discovered on screening proctosigmoidoscopy (22%). The tumors were located from the anal verge to 8 cm proximally and ranged in size from 1 to 4 cm. Pathologic findings included adenocarcinoma (92%), squamous cell carcinoma (4%), and cloacogenic carcinoma (4%). Postoperative hospitalization averaged two days (0 to 29 days). One patient died of a perioperative myocardial infarction for an operative mortality of 3 per cent. Morbidity was 7 per cent and included urinary retention and pneumonia. Postoperative radiation therapy was administered to 11 patients with either undifferentiated tumors or invasion into the muscularis propria. Follow-up in these 38 patients averaged 30 months. One patient died of metastatic carcinoma, and two patients developed local recurrence that was treated successfully by a low anterior resection or abdominoperineal resection. Transanal excision of rectal carcinoma can be performed in properly selected patients with good overall survival and local control.

Noncardiogenic pulmonary edema in dogs and cats: 26 cases (1987-1993)

Medical records of 23 dogs and 3 cats treated for noncardiogenic pulmonary edema (NPE) resulting from airway obstruction (n = 8), cranial trauma (7), electric shock (7), or seizures (4) between 1987 and 1993 were reviewed. There were 18 purebred dogs, 5 mixed-breed dogs, 2 domestic shorthair cats, and 1 Siamese. Sixteen animals were male, and 10 were female. All but 7 were less than 1 year old. Time between the inciting incident and onset of respiratory tract signs ranged from minutes to several hours. Respiratory distress was the primary clinical sign for all animals with NPE resulting from airway obstruction, cranial trauma, or seizures, and for 2 of the 7 animals with NPE resulting from electric shock. The only consistent clinicopathologic abnormality was hyperglycemia, which was detected in 12 animals. Arterial blood gas partial pressures were measured in 11 animals; 10 were hypoxemic. On thoracic radiographs, the predominant pattern of pulmonary infiltration was alveolar. Symmetry of involvement, which was assessed by examining dorsoventral or ventrodorsal radiographic projections, could be determined for 23 animals. In 18, involvement was asymmetric, and in 13 of those 18, the right side was predominantly involved. On lateral radiographic projections, the caudodorsal quadrant of the lung field was involved primarily or as part of a diffuse distribution in all but 1 animal. Generally, animals with NPE resulting from airway obstruction had the greatest degree of radiographic involvement, followed in decreasing order, by animals with NPE resulting from cranial trauma, animals with NPE resulting from seizures, and animals with NPE resulting from electric shock. Overall, 9 animals died.(ABSTRACT TRUNCATED AT 250 WORDS)

Traumatic hemoperitoneum in 28 cases: a retrospective review.

This study was conducted to evaluate and describe presenting clinical signs, course, management, and outcome of small animal patients that suffered severe traumatic hemoperitoneum. The medical records of 28 blunt trauma patients diagnosed as having hemoperitoneum and requiring the transfusion of blood products for stabilization were analyzed. The survival rate was 16/28 (57%). Six patients died from natural causes, and six patients were euthanized. Euthanized patients were not considered for the analysis of outcome. The survival rates for six animals that had surgical intervention and 16 animals that were treated medically were 67% and 75%, respectively. Statistically, larger animals had a better prognosis (p less than 0.05, unpaired t-test) for survival. Presenting clinical signs, packed cell volume (PCV), peripheral pulse rate, effusion PCV, site of intra-abdominal hemorrhage, and age were not found to correlate statistically with survival nor with the decision to perform an abdominal exploratory.

A prospective randomized trial comparing open versus laparoscopic appendectomy.

OBJECTIVE: The authors determined whether there was an advantage to laparoscopic appendectomy when compared with open appendectomy. SUMMARY/BACKGROUND DATA: The advantages of laparoscopic appendectomy versus open appendectomy were questioned because the recovery from open appendectomy is brief. METHODS: From January 15, 1992 through January 15, 1993, 75 patients older than 9 years were entered into a study randomizing the choice of operation to either the open or the laparoscopic technique. Statistical comparisons were performed using the Wilcoxon test. RESULTS: Thirty-seven patients were assigned to the open appendectomy group and 38 patients were assigned to the laparoscopic appendectomy group. Two patients were converted intraoperatively from laparoscopic appendectomies to open procedures. Thirty-one patients (81%) in the open group had acute appendicitis, as did 32 patients (84%) in the laparoscopic group. Mean duration of surgery was 65 minutes for open appendectomy and 87 minutes for laparoscopic appendectomy (p < 0.001). There were no statistically significant differences in length of hospitalization, interval until resumption of a regular diet, or morbidity. Duration of both parenteral and oral analgesic use favored laparoscopic appendectomy (2.0 days versus 1.2 days, and 8.0 days versus 5.4 days, p < 0.05). All patients were instructed to return to full activities by 2 weeks postoperatively. This occurred at an average of 25 days for the open appendectomy group versus 14 days for the laparoscopic appendectomy group (p < 0.001). CONCLUSIONS: Patients who underwent laparoscopic appendectomies have a shorter duration of analgesic use and return to full activities sooner postoperatively when compared with patients who underwent open appendectomies. The authors consider laparoscopic appendectomy to be the procedure of choice in patients with acute appendicitis.

Use of positive-pressure ventilation in dogs and cats: 41 cases (1990-1992).

Intermittent positive-pressure ventilation (PPV) is an invasive means of respiratory support that is indicated in animals with central and peripheral neuromuscular disease, as well as in those with primary disorders of the lung parenchyma. We reviewed the medical records of 34 dogs and 7 cats treated with PPV. The animals could be allotted to 2 groups; group 1 (21/41) had primary failure of ventilation attributable to neuromuscular disease or airway obstruction, and group 2 (20/41) had primary pulmonary parenchymal disease. Mean inspiratory time was 1.02 +/- 0.2 seconds (range, 0.6 to 1.5 seconds). Mean inspiratory flow was 26.9 +/- 18.5 L/min (range, 7 to 87 L/min), and was positively correlated with body weight (R = 0.57). Mean set respiratory rate was 19.6 +/- 10 breaths/min (range, 5 to 60 breaths/min), with mean tidal volume of 15.5 +/- 6.2 ml/kg of body weight. Positive end-expiratory pressure (PEEP) was required in 14 of 20 dogs in group 2. Mean peak airway pressure in group 1 was 21.6 +/- 6.3 cm of H2O, whereas in group 2 it was 32.9 +/- 12.5 cm of H2O. The higher peak airway pressure in group-2 dogs reflected poor lung compliance and the use of PEEP in dogs with parenchymal lung disease. Mean duration of PPV was 28.2 +/- 29.4 hours (range, 2 to 137 hours). The overall survival rate was 39% (16/41).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharyngeal myopathy of loaded upper airway in dogs with sleep apnea.

Recent work indicates that upper airway dilator muscles of individuals with obstructive sleep apnea syndrome (OSAS) demonstrate an increased level of activity during wakefulness compared with normal subjects. In addition, massive bursts of pharyngeal dilator activity are associated with the termination of upper airway occlusive events during sleep. This complex pattern of altered pharyngeal dilator activation is also observed in the English bulldog, an animal model of OSAS. In the present study, it was hypothesized that such alterations in activity level might lead to changes in the structure of pharyngeal muscles in the bulldog. Full-thickness biopsies were obtained from two pharyngeal dilator muscles, the sternohyoid (SH) and geniohyoid, as well as a limb muscle, the anterior tibialis, in bulldogs (n = 5) and control dogs (n = 7). Immunohistochemical analysis of myosin heavy chain expression revealed an increased contribution of fast type II myosin heavy-chain fibers to SH in bulldogs. The bulldog SH also demonstrated increased connective tissue content compared with control dogs, consistent with the presence of fibrosis. Both pharyngeal dilators in the bulldog exhibited an elevated proportion of morphologically abnormal fibers indicative of ongoing or prior injury. No differences in any of the above parameters were seen between bulldogs and control dogs in the anterior tibialis limb muscle. We conclude that the chronic load and altered pattern of usage imposed on the upper airway dilators in OSAS lead to myopathic changes that may ultimately impair the ability of these muscles to maintain pharyngeal patency.

Combined laparoscopic and endoscopic management of cholelithiasis and choledocholithiasis.

With the advent of laparoscopic cholecystectomy, optimal management of common duct stones remains controversial. Seven hundred six patients underwent laparoscopic cholecystectomy in our institution from January 1990 through January 1992. From this group of patients, 50 were identified as having clinical or radiographic evidence of common duct stones. Thirty-one patients demonstrated preoperative risk factors for common duct stones and underwent preoperative endoscopic retrograde cholangiopancreatography (ERCP). The risk factors included jaundice (19%), pancreatitis (23%), elevated liver function tests (52%), and ultrasound evidence of choledocholithiasis (6%). Preoperative ERCP was performed in 94% of patients. There were two failures due to periampullary diverticula. Common duct stones were identified in 18 patients (62%) and successfully removed by endoscopic sphincterotomy in all of these patients. Nineteen patients were found to have unsuspected common duct stones on intraoperative cholangiography. Eighteen patients (95%) underwent successful ERCP and endoscopic sphincterotomy with stone extraction. Overall, major morbidity was 2% and included one patient who experienced endoscopic sphincteroplasty. The three endoscopic failures were managed by open common duct exploration, laparoscopic duct exploration, and combined laparoscopic and open common duct exploration. We conclude that combined laparoscopic and endoscopic therapy is a viable option for the management of cholelithiasis with choledocholithiasis.