Detection of drug effects on gastric emptying and contractility using a wireless motility capsule.

BACKGROUND: A wireless motility capsule is a new method for ambulatory assessment of transit times and motility throughout the gastrointestinal tract. The objective of this study was to evaluate the ability of a wireless motility capsule to detect drug effects on gastric emptying time (GET) and gastric contractility. METHODS: 15 healthy adults were administered in random order saline, erythromycin IV 150 mg, or morphine IV 0.05 mg/kg BW. Subjects ate a standard meal after each infusion, and subsequently ingested the motility capsule. Data were recorded for 8 hours, and the results were analyzed using the manufacturer's software. RESULTS: GET was significantly faster after erythromycin than either saline or morphine. Morphine tended to delay emptying of the capsule compared to saline. There was a trend toward a greater frequency of gastric contractions with erythromycin and a reduced frequency of gastric contractions with morphine that did not reach statistical significance. CONCLUSIONS: A wireless motility capsule successfully detected acceleration of gastric emptying induced by erythromycin, and retardation of gastric motility caused by morphine. These results indicate that a wireless motility capsule is a promising technique to assess pharmacologic effects on gastric transit and contractility and aid in development of drugs for gastric motor disorders.

Do patients at risk of sleep apnea have an increased risk of cardio-respiratory complications during endoscopy procedures?

BACKGROUND: Patients with sleep apnea (OSA) have an increased risk of perioperative complications. AIM: The purpose of this study is to assess whether OSA increases the risk of cardio-respiratory complications in patients undergoing endoscopic procedures with conscious sedation. METHODS: A prospective study over a 7-month period was performed. All patients undergoing upper, lower, or combined endoscopy were asked to fill in the Berlin questionnaire. The questionnaire was scored, and patients were classified as high or low risk for sleep apnea based on the suggested scoring criteria. Patients who had previously undergone a sleep study were excluded. Demographics and co-morbidities were identified from the electronic medical record. Procedure type, amount of sedation, and minor and major complications were identified from the endoscopy flow sheet. The minor complications were defined as hypertension, hypotension, bradycardia, tachycardia, hypoxemia, and bradypnea (respiratory rate <8 breaths/min). Major complications included chest pain, arrhythmia, altered mental status, respiratory distress, and a minor complication that required a significant intervention, such as use of a reversal agent, atropine, up-titration of oxygen for hypoxemia, or prolonged observation. RESULTS: Procedures were performed in 904 patients: colonoscopies, 68.0%; upper endoscopies, 22.8%; and combined procedures, 9.2%. Five hundred fifty-three patients were identified as low risk (61.2%), and 351 were identified as high risk (38.8%). The mean age was 59.5 ± 10.5 years, mean body mass index was 28.9 ± 6.6, mean neck circumference was 16.2 ± 6.3 in., and 91.4% were males. The median Charlson co-morbidity index was 1 (25-75% percentage range 0-2). All patients received midazolam and fentanyl during endoscopy. The median and 25-75% range for midazolam and fentanyl dosages were 5 mg, 4-6 mg and 100 µg, 75-125 µg, respectively. Minor complications were observed in 10.56% of low-risk patients and 10.63% of high-risk patients (p = not significant (NS); odds ratio, 1.01; 95% confidence interval 0.65-1.56). Major complications were observed in 3.25% of low-risk patients and 1.9% of high-risk patients (p = ns; odds ratio, 0.6; 95% confidence interval 0.26-1.46). CONCLUSION: For patients undergoing endoscopy procedures under conscious sedation, the presence of OSA does not clearly increase the risk of cardiopulmonary complications.

Does sleep apnea increase the risk of cardiorespiratory complications during endoscopy procedures?

BACKGROUND: Patients with obstructive sleep apnea (OSA) have an increased risk of perioperative complications. AIM: The purpose of this study is to assess whether OSA increases the risk of cardiorespiratory complications in patients undergoing endoscopic procedures. METHODS: A retrospective study was performed. We identified all patients who had undergone both an endoscopic procedure under conscious sedation and a sleep study from January 2001 to May 2008. Patients were divided into four groups: OSA negative (apnea-hypopnea index (AHI) < 5/h), OSA positive; mild: AHI 5-15/h, moderate: AHI 15.1-30/h, and severe: AHI > 30/h. Minor and major complications were identified. The minor ones were hypertension, hypotension, bradycardia, tachycardia, oxygen desaturation (<90%), and bradypnea. Major complications included chest pain, respiratory distress, cardiorespiratory arrest, or any minor complication that required intervention. RESULTS: Procedures were performed in 639 patients: colonoscopies 68.5%, upper endoscopies 20.2%, and combined procedures 11.3%. The mean age was 60.5 years, mean body mass index 33.7, and 93% were males. Sleep study results: 130 negative, 509 positive; 135 mild, 125 moderate, and 249 severe. Of the patients, 19% had minor complications, while 7% had major complications. There was no significant difference between the patients with and without OSA in the rate of minor complications (odds ratio 1.17, 95% confidence interval 0.70-1.92) or major complications (odds ratio 1.19, 95% confidence interval 0.54-2.63). The odds ratio was also not significantly increased when a cutoff value of 10 or 15/h was used to delineate a positive sleep study. CONCLUSION: For patients undergoing endoscopy procedures under conscious sedation, the presence of OSA does not clearly increase the risk of cardiorespiratory complications.

Thyroid hormone responsive protein (THRP) mediates thyroid hormone-induced cytotoxicity in primary neuronal cultures.

The thyroid hormone responsive protein (THRP) is a novel gene product that remains responsive to thyroid hormone (TH) in the cerebral cortex of adult rats. To study the effects of THRP on neuronal cell survival, primary neurons cultured from rats at embryonic day 19 were treated with either 10(-7) mol L(-1) 3,5,3'-triiodothyronine (T(3)), or 10(-7) mol L(-1) L: -thyroxine (T(4)). This resulted in decreasing neuronal cell number starting 48 h after treatment. T(3) -related cytotoxicity was also documented by measurement of lactate dehydrogenase release into the medium and by propidium iodide staining. Treatment of cells with 10(-7) mol L(-1) T(3) resulted in a significant increase in THRP mRNA levels as early as 24 h of treatment in a concentration-dependent manner. T(3) treatment did not alter glyceraldehyde 3-phosphate dehydrogenase (G3PDH) mRNA levels. Exogenous expression of THRP by transfecting cells with a THRP expression construct (pSVL-THRP) was associated with a significant increase in cell death as measured by the increased number of propidium iodide staining cells (18.0+/-2.1 cells per field) compared with mock-transfected cells (3.3+/-0.2), P<0.002. To further document THRP-induced cytotoxicity, the cells were either transfected with pSVL (empty vector)+pSV2neo (neomycin resistance vector for cell labeling), pSVL-THRP+pSV2neo, or pSVL-THRP+pc-Abl (cAbl tyrosine kinase expressing vector)+pSV2neo. After 24 h the cells were treated with 500 microg mL(-1) G418 (a congener of neomycin) to eliminate the non-transfected cells. Transfection with pSVL-THRP reduced neuronal survival relative to cells transfected with pSVL (356+/-15.6 compared with 145+/-16.9, P<0.05). Co-transfection of THRP with wild-type c-Abl did not alter the effect of THRP on cell survival. It is concluded that THRP is an important factor in TH-induced neuronal cell death.

Microarray analysis of thyroid hormone-induced changes in mRNA expression in the adult rat brain.

To determine which genes in the adult rat brain are regulated by thyroid hormone (TH), we used microarrays to examine the effect of hyperthyroidism on neuron-specific gene expression. Four-month-old male Fisher 344 rats were rendered hyperthyroid by intraperitoneal injection of 3,5,3'-L-triiodothyronine (T3, 15 microg/100 g body weight) for 10 consecutive days. To minimize interindividual variability, pooled cerebral tissue RNA from four-control and five-hyperthyroid rats was hybridized in duplicates to the Affymetrix (Santa Clara, CA) U34N rat neurobiology microarray, which contains probes for 1224 neural-specific genes. Changes in gene expression were considered significant only if they were observed in both pair-wise comparisons as well as by Northern blot analysis. Hyperthyroidism was associated with modest changes in the expression of only 11 genes. The expression of the phosphodiesterase Enpp2, myelin oligodendrocyte glycoprotein (Mog), microtubule-associated protein 2 (MAP2), growth hormone (GH), Ca(2+)/calmodulin-dependent protein kinase beta-subunit (Camk2b), neuron-specific protein PEP-19 (Pcp4), a sodium-dependent neurotransmitter, and the myelin-associated glycoprotein (S-MAG) was significantly increased. Three genes were suppressed by hyperthyroidism, including the activity and neurotransmitter-induced early genes-1 and -7 (ANIA-1 and ANIA-7) and the guanine nucleotide-binding protein one (Gnb1). The present study underscores the paucity of TH responsive genes in adult cerebral tissue.

Suppression of apolipoprotein AI gene expression in HepG2 cells by TNF alpha and IL-1beta.

Plasma inflammatory cytokines are elevated in obese subjects as well as in those with type 2 diabetes. This presumably results in systemic insulin resistance, characterized by a pro-atherogenic plasma lipid profile and reduced apolipoprotein AI (apoAI) protein levels. To determine how cytokine-mediated insulin resistance suppresses apoAI gene expression, we investigated the effect of tumor necrosis factor alpha (TNF alpha) and interleukin-1beta (IL-1beta) on apoAI protein, mRNA, and transcriptional activity in the human hepatoma cell line HepG2. ApoAI secretion was suppressed in a dose-dependent manner in HepG2 cells treated with both cytokines. ApoAI protein levels were 2892+/-22.0, 2263+/-117, 2458+/-25.0, 3401+/-152, 2333+/-248, 1520+/-41.5 and 956.0+/-11.0 arbitrary units (AU) in cells treated with 0, 0.3, 1.0, 3.0, 10, 30, and 100 ng/ml TNF alpha, achieving statistical significance in the 30 and 100 ng/ml range (P<0.0009). ApoAI protein levels were 4055+/-360, 3697+/-101, 3347+/-327, 1561+/-33.0, 1581+/-182, 810.0+/-59.5, and 1766+/-717 AU in cells treated with similar doses of IL-1beta, achieving statistical significance within the range of 3-100 ng/ml (P<0.02). ApoAI mRNA levels were suppressed 50.8% in HepG2 cells treated with 30 ng/ml TNF alpha for 24 h (P<0.05), and remained suppressed for up to 96 h. Similarly, treatment of cells with 30 ng/ml IL-1beta for 24 h, resulted in 42.9% reduction in apoAI mRNA levels (P<0.05) and remained suppressed for up to 96 h. In order to determine if the effect of TNF alpha and IL-1beta occurs at the transcriptional level, HepG2 cells were transfected with a chloramphenicol acetyltransferase (CAT) reporter gene plasmid containing the full-length apoAI promoter, and after 24 h, treated with TNF alpha (30 ng/ml), IL-1beta (30 ng/ml), or both cytokines. CAT activity was suppressed by both cytokines (24.0+/-1.9% acetylation in control cells vs. 5.6+/-1.2% (P<0.0004), 10.2+/-1.5% (P<0.0006), and 3.9+/-0.9% acetylation (P<0.0002) in cells treated with TNF alpha, IL-1beta, and the combination of both cytokines, respectively) suggesting that cytokine-mediated suppression occurs at the transcriptional level. Using a series of apoAI deletion constructs, the cytokine response element was mapped between nucleotides -325 and -186 (relative to the transcriptional start site). This region contains a previously identified and characterized cis-element, site A, which binds several different transcription factors. Finally, electrophoretic mobility shift assays (EMSA) showed that TNF alpha treatment of HepG2 cells is associated with reduced nuclear factor binding to site A. These studies suggest that inflammatory cytokines down-regulate apoAI expression at least partly through inhibition of binding of the nuclear factors to site A of the apoAI promoter.