Incretin dysfunction and hyperglycemia in cystic fibrosis: Role of acyl-ghrelin

BackgroundInsulin secretion is insufficient in cystic fibrosis (CF), even before diabetes is present, though the mechanisms involved remain unclear. Acyl-ghrelin (AG) can diminish insulin secretion and is elevated in humans with CF.MethodsWe tested the hypothesis that elevated AG contributes to reduced insulin secretion and hyperglycemia in CF ferrets.ResultsFasting AG was elevated in CF versus non-CF ferrets. Similar to its effects in other species, AG administration in non-CF ferrets acutely reduced insulin, increased growth hormone, and induced hyperglycemia. During oral glucose tolerance testing, non-CF ferrets had responsive insulin, glucagon like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels and maintained normal glucose levels, whereas CF ferrets had insufficient responses and became hyperglycemic. Interestingly in wild-type ferrets, the acyl-ghrelin receptor antagonist [D-Lys3]-GHRP-6 impaired glucose tolerance, and abolished insulin, GLP-1, and GIP responses during glucose tolerance testing. By contrast, in CF ferrets [D-Lys3]-GHRP-6 improved glucose tolerance, enhanced the insulin-to-glucose ratio, but did not impact the already low GLP-1 and GIP levels.ConclusionsThese results suggest a mechanism by which elevated AG contributes to CF hyperglycemia through inhibition of insulin secretion, an effect magnified by low GLP-1 and GIP. Interventions that lower ghrelin, ghrelin action, and/or raise GLP-1 or GIP might improve glycemia in CF.     

Hepatitis E virus detected from Chinese laboratory ferrets and farmed mink

A novel genotype of hepatitis E virus (HEV ) has been discovered in ferrets and mink worldwide. However, the situation in China is unknown. Diverse HEV RNA belonging to HEV genotype C2 was detected in this study from 17.5% (18/103) of the laboratory ferrets and 1.9% (2/107) of farmed mink in China. Phylogenetic analysis showed that the ferret HEV strains clustered into three groups with known strains detected from the United States and the Netherlands. Attempted transmission of ferret HEV to two rabbits was not successful. This study confirmed that the C2 genotype of HEV is circulating in China and succeeded in infecting laboratory ferrets with this genotype of HEV . Further studies are required to determine whether the C2 genotype of HEV can infect humans.     

Characterization of H7N9 avian influenza viruses isolated from duck meat products

Avian influenza H7N9 viruses have caused five epidemic waves of human infections since the first human cases were reported in 2013. In 2016, the initial low pathogenic avian influenza (LPAI) H7N9 viruses became highly pathogenic, acquiring multi‐basic amino acids at the haemagglutinin cleavage site. These highly pathogenic avian influenza (HPAI) H7N9 viruses have been detected in poultry and humans in China, causing concerns of a serious threat to global public health. In Japan, both HPAI and LPAI H7N9 viruses were isolated from duck meat products carried illegally and relinquished voluntarily at the border by passengers on flights from China to Japan between 2016 and 2017. Some of the LPAI and HPAI H7N9 viruses detected at the border in Japan were characterized previously in chickens and ducks; however, their pathogenicity and replicative ability in mammals remain unknown. In this study, we assessed the biological features of two HPAI H7N9 virus isolates [A/duck/Japan/AQ‐HE29‐22/2017 (HE29‐22) and A/duck/Japan/AQ‐HE29‐52/2017 (HE29‐52); both of these viruses were isolated from duck meat at the border)] and an LPAI H7N9 virus isolate [A/duck/Japan/AQ‐HE28‐3/2016 (HE28‐3)] in mice and ferrets. In mice, HE29‐52 was more pathogenic than HE29‐22 and HE28‐3. In ferrets, the two HPAI virus isolates replicated more efficiently in the lower respiratory tract of the animals than did the LPAI virus isolate. Our results indicate that HPAI H7N9 viruses with the potential to cause severe diseases in mammals have been illegally introduced to Japan.     

Pretreatment with ondansetron blunts plasma vasopressin increases associated with morphine administration in ferrets

Postoperative nausea and vomiting are significant problems. A method for measuring vomiting thresholds for anesthetics using plasma markers, such as arginine vasopressin (AVP), would be useful. We measured the change in AVP concentrations associated with morphine alone or in combination with ondansetron pretreatment. Data were collected from ferrets implanted with IV catheters. After recovery, the ferrets were administered IV morphine alone or with ondansetron pretreatment. Baseline blood samples were taken before morphine injection, and at 5, 10, 15, 30, 45, 60, and 90 min after morphine injection. Plasma AVP levels were measured using radioimmunoassay. Morphine alone was associated with a significant increase in plasma AVP concentrations from baseline at 45, 60, and 90 min (P < 0.05). Ondansetron alone did not change the plasma AVP concentration after 20 min (P > 0.46). There was no significant increase (P > 0.46) in AVP concentration in animals that were pretreated with ondansetron before administration of morphine. Two-way analysis of variance confirmed that ondansetron significantly decreased the increase in AVP by morphine at 60 and 90 min (P < 0.05). These data suggest that plasma AVP concentration may be an accurate marker for nausea, and may be useful to guide treatment for this condition. IMPLICATIONS: The antiemetic, ondansetron, has an effect not only on clinically perceived vomiting, but also on plasma vasopressin level.     

Effects of dexmedetomidine on contractility, relaxation, and intracellular calcium transients of isolated ventricular myocardium

The effects of the highly selective alpha 2-adrenoceptor agonist dexmedetomidine on contractility, relaxation, and the intracellular Ca2+ transients of isolated ventricular myocardium were studied in isolated right ventricular papillary muscles obtained from reserpinized ferrets. Dexmedetomidine (10(-10)-10(-5) M) did not alter amplitude and time variables of isometric, isotonic and zero-load-clamped twitches, except for a slight increase in maximal isotonic relaxation rate at 10(-5) M. Dexmedetomidine (10(-8)-10(-5) M) caused no changes in the intracellular Ca2+ transient detected with aequorin. These results suggest that dexmedetomidine has no intrinsic myocardial contractile effects.     

Alterations in the course of and histopathologic response to influenza virus infections produced by enflurane, halothane, and diethyl ether anesthesia in ferrets

Alterations in the course of and histopathologic response to influenza viral infections by halothane, enflurane, and diethyl ether anesthesia were evaluated in ferrets. There were no significant differences in the incidence and duration of lethargy, pyrexia, rhinorrhea, or sneezing in infected animals given one of the three anesthetic agents under investigation, compared with those receiving no anesthesia. There were no differences in lung pathology in infected animals given one of the three anesthetic agents, or no anesthesia, though histopathologic changes in the nasal turbinates were significantly greater in ferrets given enflurane. This study suggests that general anesthesia administered to ferrets infected with influenza virus carries minimal morbidity, although enflurane anesthesia was found to produce greater histopathologic changes than the other agents.     

Serorrhaphy prevents regeneration of vagus nerve fibers after proximal gastric vagotomy

Spouting or regeneration of vagus fibers occurs after vagotomy. An axonal tracing method was used to see the long-term effect of serorrhaphy in the prevention of axonal regeneration after proximal gastric vagotomy (PGV) in ferrets. METHODS: A neurotracer, wheat-germ agglutinin-horseradish peroxidase (0.5 mg), was injected subserosally at the corpus of the anterior stomach (1) without PGV (n = 4), (2) immediately after PGV (n = 2), (3) one year after PGV with serorrhaphy (n = 3), and (4) one year after PGV without serorrhaphy (n = 3). The ferrets were killed by perfusion-fixation. The brainstem was processed histochemically. Numbers of labeled cells in the dorsal motor nucleus of the vagus were statistically analyzed using square-root transformation. RESULTS: Numbers of labeled cells were 348 for (1), 13 for (2), 2 for (3), and 43 for (4). Multiple comparisons revealed significant differences in (1) vs. (2), (3), (4) and (3) vs. (4). DISCUSSION: The number of preganglionic efferent vagus cells decreased acutely after PGV, which persisted one year. Regenerated vagus axons were less in the chronic group with serorrhaphy than in the group without one. Thus time factor did not influence the regeneration, but serorrhaphy was important in preventing vagal regeneration. CONCLUSION: Serorrhaphy during PGV prevents the regeneration of preganglionic efferent vagus fibers.     

The effects of general anesthesia on upper respiratory tract infections in children

A prospective cohort study of 489 pediatric patients was performed to investigate the prevalence of perioperative respiratory complications and symptomatology in children presenting for myringotomy with upper respiratory tract infections (URIs). All children undergoing myringotomy received halothane N2O/O2 anesthesia administered via face mask. Information on complications and respiratory symptoms was obtained from the anesthesia and recovery room records, and by standardized questionnaire. There were no significant differences in perioperative complications between asymptomatic children (1.23%), symptomatic children fulfilling predetermined URI criteria (1.28%), and symptomatic children that did not fulfill the URI criteria (2.38%). In addition, the prevalence and duration of respiratory symptoms was significantly less in children having received anesthesia and surgery than in a matched group of non-anesthetized controls who did not have surgery. Results from this study suggest that there is no increased morbidity for children presenting at minor surgery with acute uncomplicated URIs and who did not require tracheal intubation. In addition, the administration of general anesthesia and surgery to this group of patients was followed by a decrease in both the appearance and duration of a number of respiratory symptoms.     

The effect of intrathecal fentanyl added to hyperbaric bupivacaine on maternal respiratory function during Cesarean section

BACKGROUND: Subarachnoid blockade with local anesthetics induces respiratory depression. Although the addition of fentanyl to bupivacaine has become popular in subarachnoid blockade for Cesarean section, there is no information on the effect of intrathecal fentanyl on maternal spirometric respiratory function in parturients undergoing Cesarean section. METHODS: We tested the effect of the addition of intrathecal fentanyl to hyperbaric bupivacaine on maternal spirometric performance in 40 consenting parturients undergoing Cesarean section. The parturients were randomized into two groups: those receiving 2.0 ml of hyperbaric bupivacaine 0.5% and 0.4 ml of saline intrathecally and those receiving 2.0 ml of hyperbaric bupivacaine and 0.4 ml of fentanyl (20 microg) intrathecally. We performed spirometry on arriving at the operation room and 15 min after subarachnoid blockade. RESULTS: Subarachnoid blockade with bupivacaine significantly decreased the peak expiratory flow rate, but did not induce significant changes in vital capacity and forced vital capacity. The addition of intrathecal fentanyl to bupivacaine improved the quality of subarachnoid blockade, but did not lead to a deterioration in respiratory function compared with intrathecal bupivacaine alone. CONCLUSIONS: The addition of intrathecal fentanyl to hyperbaric bupivacaine did not lead to a deterioration in maternal spirometric respiratory function in parturients undergoing Cesarean section.     

Respiratory deficiency in experimental idiopathic scoliosis

Clinically significant respiratory failure in a group of animals with an experimentally produced structural thoracic scoliosis was identified. A detailed physiologic investigation of their respiratory function showed that their respiratory compromise was associated with the development of a smaller and stiffer chest. Frank respiratory failure, however, was rare and seen only in animals with the most severe spinal deformities when it was also associated with a general failure to thrive. Animals with less severe deformities had little measurable restriction of pulmonary function, did not develop respiratory failure, and grew normally.     

Indoprofen, a non-steroidal anti-inflammatory analgesic which does not depress respiration in normal man. A study comparing indoprofen with morphine

The respiratory effects of intravenous indoprofen 400 mg, a highly effective non-steroidal anti-inflammatory analgesic, were compared with those of morphine 10 mg in 10 healthy volunteers. Morphine exhibited its characteristic adverse respiratory depressant properties, Indoprofen, in contrast, did not influence the subjects' breathing pattern.     

Accounting for intubation status in predicting mortality for victims of motor vehicle crashes

BACKGROUND: Two of the important predictors of mortality for trauma patients are the Glasgow Coma Scale and the respiratory rate. However, for intubated patients, the verbal response component of the Glasgow Coma Scale and the respiratory rate cannot be accurately obtained. This study extends previous work that attempts to predict mortality accurately for intubated patients without using verbal response and respiratory rate. METHODS: The New York State Trauma Registry was used to identify 1994 and 1995 victims of motor vehicle crashes (MVCs). For the subset of patients who were not intubated, we developed two statistical models to predict mortality: one did not contain verbal response or respiratory rate, and the other contained a predicted verbal response. These were compared with a model that did include verbal response and respiratory rate. We also compared the predictive abilities of the first two models for all MVC patients (intubated and nonintubated) and determined the extent to which intubated patients were at increased risk of dying in the hospital after having adjusted for other predictors of mortality. RESULTS: For nonintubated patients, the statistical model without verbal response and the model with predicted verbal response had slightly better discrimination and worse calibration than the model that included verbal response and respiratory rate. Predicted verbal response did not improve the strength of the model without verbal response. For all MVC patients (intubated and nonintubated), predicted verbal response was not a significant predictor of mortality when used in combination with the other predictors. Intubation status was a significant predictor, with intubated patients having a higher probability of dying in the hospital than patients with otherwise identical risk factors. CONCLUSION: Inpatient mortality for intubated MVC patients can be accurately predicted without respiratory rate or verbal response. There appears to be no need for predicted verbal response to be part of the prediction formula, but intubation status is an important independent predictor of mortality and should be used in statistical models that predict mortality for MVC patients.     

The respiratory effect of doxapram and pentazocine and their interaction (author's transl)]

A 2X2 factorially designed study has been done to determine the respiratory effects of pentazocine and doxapram in terms of the minute ventilation end-expiratory PCO2 response curve. Pentazocine 30 mg intramuscularly produced marked respiratory depression. Doxapram 60 mg intramuscularly produced significant respiratory stimulation. When this dose of doxapram was given in combination with 30 mg pentazocine it produced significant reduction in the amount of respiratory depression induced by the narcotic. The statistical analysis did not show that there was anything to suggest this effect was more than additive.     

Respiratory symptoms, asthma, exercise test spirometry, and atopy in schoolchildren from a Lima shanty town

BACKGROUND: Little is known about the associations between symptoms of asthma, pulmonary function tests, and atopy in developing countries. While asthma in children is often associated with atopy, some studies of wheezing illness have found little or no association, leading to suggestions that there are subgroups of wheezing illness. The ISAAC study recently reported that the prevalence of reported asthma symptoms in Lima, Peru was among the highest in the world, but did not report on the atopic status of the subjects. METHODS: A cross sectional survey was conducted of children aged 8-10 years who had previously participated in a cohort study of respiratory and diarrhoeal illnesses in infancy. Questionnaires were administered asking about respiratory symptoms and asthma diagnoses, pulmonary function tests were performed before and after exercise on a treadmill, and atopy was determined from skin prick tests and specific serum IgE levels. RESULTS: A total of 793 children participated in the survey. The prevalence of asthma related symptoms in the last 12 months was 23.2%, but only 3.8% of children reported a recent asthma attack. The mean differences in pretest percentage predicted forced expiratory volume in one second (FEV(1)) were 8.1% (95% CI 2.4 to 13.8) between children who did and did not report an asthma attack in the last 12 months, and 5.3% (95% CI 2.8 to 7.9) in children who did and did not report respiratory symptoms. The corresponding differences in mean percentage fall in FEV(1) after exercise were 3.1% (95% CI -1 to 7.1) and 5.1% (95% CI 3.4 to 6.8). Recent asthma or respiratory symptoms were not associated with atopy in this population (odds ratios 1.29 (95% CI 0.56 to 2.97) and 0.91 (95% CI 0.61 to 1.37), respectively). CONCLUSIONS: Most asthma in these children was unrecognised and mild. Asthma and asthma symptoms in this population do not seem to be related to atopy.     

A motion-sensitive area in ferret extrastriate visual cortex: an analysis in pigmented and albino animals

In search of the neuronal substrate for motion analysis in the ferret (Mustela putorius furo), we extracellularly recorded from extrastriate visual cortex in five pigmented and two albino ferrets under general anaesthesia and paralysis. Visual stimulation consisted of large area random dot patterns moving either on a circular path in the frontoparallel plane or expanding and contracting radially. Strongly direction-selective neurons were recorded in a circumscribed area in and just posterior to the suprasylvian sulcus, thus named by us the posterior suprasylvian area (area PSS). Altogether, we recorded 210 (90%) and 95 (72%) PSS neurons in pigmented and albino ferrets, respectively, that were direction selective. In these neurons responses during random dot pattern stimulation in the preferred direction were at least twice as strong than stimulation in the non-preferred direction. Response strength in preferred direction and tuning sharpness of PSS neurons in albinos were significantly reduced when compared to pigmented animals (median values: 34.1 versus 14.8 spikes/s and 142 versus 165 degrees for pigmented and albino ferrets, respectively). Inter-spike-intervals during visual stimulation were significantly shorter in pigmented (median 9 ms) than in albino PSS neurons (median 14 ms). Our data indicate that area PSS may play a crucial role in motion perception in the ferret.     

Effect of endoscopic sinus surgery on pulmonary status of adults with cystic fibrosis

Objective Functional endoscopic sinus surgery (FESS) provides symptomatic relief of sinus disease in patients with cystic fibrosis (CF), but it is unclear whether it has beneficial effects on lung disease in this population. This study assessed the effect of FESS on the respiratory status of adult patients with CF. Study Design Retrospective chart review. Setting Tertiary medical center. Subjects Thirty-two adult patients with CF who underwent 45 operative cases. Methods Clinical information retrieved for the 12-month periods preceding and following to determine the effect of FESS on the rate of decline in lung function, as well as intravenous antibiotic use and hospitalization for pulmonary exacerbation. Results The rate of decline in forced expiratory volume in 1 second and forced vital capacity was not significantly different in the 12 months before and after FESS. Functional endoscopic sinus surgery did not reduce days hospitalized or days on intravenous antibiotics for a respiratory exacerbation in the pre- vs postoperative period. Limiting the analysis to the 30 surgeries that were performed in patients with concomitant respiratory symptoms (ie, excluding the 15 surgeries performed for sinus symptoms alone) did not significantly alter the results. Covariates of importance in CF, including CFTR genotype, gender, or microbiology, did not affect the study results. Conclusion These results did not demonstrate an effect of FESS on progression of lung disease in patients with CF, but further research is needed because low statistical power has made some of the negative findings inconclusive.     

How do diazepam and flumazenil influence respiratory control by the activities of both hypoglossal and phrenic nerves in rabbits?

BACKGROUND: Upper airway obstruction and inadequate ventilation often arise during sedation and anesthesia by benzodiazepines. To estimate the influence of benzodiazepines on the respiratory control, we studied the effect of diazepam and flumazenil on the neural activity and the respiratory response caused by a brief (60 sec) respiratory arrest (RA) observed in the hypoglossal nerve (HG) and phrenic nerve (PH) in rabbits. METHODS: Experiments were preformed on adult rabbits vagotomized, paralyzed and ventilated artificially with 50% N2O, 50% oxygen and 0.3-0.5% sevoflurane. We evaluated and compared the effects of diazepam and flumazenil on the peak amplitude (AMP-HG&PH) and the root mean square (RMS-HG&PH) of HG and PH, and respiratory cycle (Tc). RESULTS: Diazepam depressed HG activity more than PH activity with no influence on Tc. But it did not cause dose-related depression. Flumazenil 0.2 mg.kg-1 completely reversed the respiratory depressions caused by diazepam with the increased Tc. In addition to augmentation of the hypoglossal activity in inspiration, flumazenil caused a rise in its activity in pan-expiratory period in some cases. Additional administration of diazepam 6 mg.kg-1 following flumazenil depressed PH activity again, but did not affect HG activity any more. There was no significant depression in cardiovascular parameters with tested dosages of diazepam and flumazenil. RA response was characterized by raised AMPs and augmented RMSs (delta AMPs, delta RMSs) with marked prolongation in Tc (delta Tc). Diazepam depressed RA response dose dependently, but flumazenil did not seem to antagonize this depression. CONCLUSIONS: These results suggest that 1) flumazenil is not only a specific antagonist of benzodiazepines but also a potential excitatory agent of hypoglossal nerve activity, and that 2) there is some functional diversity in disposition of benzodiazepine-receptor binding GABAA-receptor responsible for neural respiratory control system.     

Failure of nalbuphine to antagonize morphine: a double-blind comparison with naloxone

The authors studied the respiratory and analgesic effects of nalbuphine (0.21 mg/kg, intravenous), naloxone (0.014 mg/kg, intravenous), and placebo (normal saline) when given after morphine (0.21 mg/kg, intravenous) in a double-blind, randomized fashion. Resting end-tidal CO2 (PETCO2), ventilatory and occlusion pressure responses to CO2 rebreathing, and pain threshold were measured in 12 healthy adult volunteers before, 5 min, and 30 min after morphine. Nalbuphine, naloxone, or saline were administered 55 min after morphine, and the above measurements were repeated 5 min later (60 min after morphine) as well as 90, 120, 180, and 240 min after morphine. Whereas naloxone reversed respiratory depression as measured by all three respiratory parameters, nalbuphine either further depressed (resting PETCO2) or did not affect (ventilatory and occlusion pressure responses to CO2 rebreathing) respiratory drive. Morphine produced a significant elevation of the pain threshold. Significant decreases in the pain threshold were seen only after naloxone. Saline and nalbuphine did not significantly alter the pain threshold. The data indicate that nalbuphine may not reliably antagonize moderate doses of morphine.     

Sedation with sufentanil in patients receiving pressure support ventilation has no effects on respiration: a pilot study

PURPOSE: To evaluate the effects of sedation with sufentanil on respiratory drive, respiratory pattern, and gas exchange of critically ill patients during pressure support ventilation. METHODS: In this prospective observational cohort study, we observed 12 adult patients receiving partial ventilatory support for acute respiratory failure. Each subject received a continuous infusion of sufentanil at 0.2 to 0.3 micro g x kg(-1) x hr(-1) to obtain a modified Ramsay sedation score between 2 and 3. In basal conditions and at variable distance from the beginning of the sufentanil infusion (10', 30', 60', 120', 24 hr) we evaluated gas exchange, hemodynamic variables, respiratory rate (RR), tidal volume (TV), respiratory pattern, respiratory drive (P0.1) and inspiratory impedance of the respiratory system [P0.1/TV/inspiratory time (Ti)]. RESULTS: The continuous iv administration of 0.2 to 0.3 micro g x kg(-1) x hr(-1) of sufentanil resulted in the desired level of sedation. No significant heart rate, heart rhythm and blood pressure changes were observed. Sufentanil infusion did not affect TV, minute volume, Ti/inspiratory duty cycle, RR, P0.1, P0.1/TV/Ti and gas exchange did not change significantly over the study period. CONCLUSION: A continuous infusion of sufentanil induces "awake" sedation with no detectable effects on respiratory variables in critically ill patients during partial ventilatory support.     

Postoperative respiratory arrhythmias: incidence and measurement

BACKGROUND: Postoperative respiratory disturbances may be the result either of depression of respiratory drive, or alteration of respiratory pattern. METHODS: Using an inductance plethysmograph, we continuously recorded the breathing in 52 patients for 4 h after major thoracic, abdominal, and body surface surgery. The ventilatory response to hypercapnia was measured preoperatively, and at the start and end of the observation period. RESULTS: From a variety of statistical measures of respiratory depression, it was found that the occurrence of apnoeas (breath times >10 s), did not correlate with measures of respiratory drive, or with dose or route of administration of opioid, site of surgery, pain, or drowsiness. Instead, the incidence of apnoeas correlated most closely with measures of respiratory pattern (standard deviation of breath times (r=0.72), the mean breath time (r=0.63), approximate entropy of the breath times (r= -0.32)). Twenty-nine percent of patients had some breath times (Ttot) longer than 20 s. CONCLUSION: We would conclude that changes in respiratory pattern are not closely correlated with changes in traditional measures of respiratory drive.