Undetected Respiratory Depression in People with Opioid Use Disorder.

BACKGROUND: Opioid-related deaths are increasing globally. Respiratory complications of opioid use and underlying respiratory disease in people with Opioid Use Disorder (OUD) are potential contributory factors. Individual variation in susceptibility to overdose is, however, incompletely understood. This study investigated the prevalence of respiratory depression (RD) in OUD treatment and compared this to patients with chronic obstructive pulmonary disease (COPD) of equivalent severity. We also explored the contribution of opioid agonist treatment (OAT) dosage, and type, to the prevalence of RD. METHODS: There were four groups of participants: 1) OUD plus COPD ('OUD-COPD', n = 13); 2) OUD without COPD ('OUD', n = 7); 3) opioid-naïve COPD patients ('COPD'n = 13); 4) healthy controls ('HC'n = 7). Physiological indices, including pulse oximetry (SpO2%), end-tidal CO2 (ETCO2), transcutaneous CO2 (TcCO2), respiratory airflow and second intercostal space parasternal muscle electromyography (EMGpara), were recorded continuously over 40 min whilst awake at rest. Significant RD was defined as: SpO2%< 90% for > 10 s, ETCO2 per breath > 6.6 kPa, TcCO2 overall mean > 6 kPa, respiratory pauses > 10 s RESULTS: At least one indicator was observed in every participant with OUD (n = 20). This compared to RD episode occurrence in only 2/7 HC and 2/13 COPD participants (p < 0.05,Fisher's exact test). The occurrence of RD was similar in OUD participants prescribed methadone (n = 6) compared to those prescribed buprenorphine (n = 12). CONCLUSIONS: Undetected RD is common in OUD cohorts receiving OAT and is significantly more severe than in opioid-naïve controls. RD can be assessed using simple objective measures. Further studies are required to determine the association between RD and overdose risk.

COPD and asthma in patients with opioid dependency: a cross-sectional study in primary care.

Patients treated for drug addiction have high asthma and COPD prevalence rates. The relative contributions of cigarette smoking, smoking intensity and possible smoking of other substances has not been described. We aimed to describe the prevalence and determinants of asthma and COPD in patients prescribed methadone as opioid substitution therapy (OST). In a cross-sectional study of an anonymised patient-level primary care dataset of UK inner-city general practices (n = 46), 321,395 patients aged ≥18 years were identified. A total of 676 (0.21%) had a record of a methadone ever issued in primary care. The association between respiratory disease and methadone prescribing was examined using logistic regression. Models were adjusted for potential effects of clustering by practice. A total of 97.3% of patients prescribed methadone were cigarette smokers, either current (81.2%) or ex-smokers (16.1%). The prevalences of asthma and COPD were higher in methadone patients (14.2% and 12.4%, respectively) compared to non-methadone patients (4.4% and 1.1%, respectively). Methadone was an independent determinant of asthma, adjusting for smoking status (OR 3.21; 95% CI: 2.52, 4.10) or for smoking intensity (3.08; 2.27, 4.19), and of COPD, adjusting for smoking status (6.00; 4.61, 7.80) or for smoking intensity (5.80; 4.12, 8.17). COPD and asthma prevalence were substantially higher in those prescribed methadone compared to those never prescribed methadone. Prescription of methadone was an independent predictor for both COPD and asthma, even after adjustment for smoking status and smoking intensity. Possible explanations include confounding by association with smoking of heroin or crack cocaine, both of which may have a causal association with COPD and asthma.

Mirtazapine for chronic breathlessness? A review of mechanistic insights and therapeutic potential.

INTRODUCTION: Chronic breathlessness is a common and distressing symptom of advanced disease with few effective treatments. Central nervous system mechanisms are important in respiratory sensation and control. Consequently, drugs which may modify processing and perception of afferent information in the brain may have a role. Antidepressants have been proposed; however, current evidence is limited. Of potentially suitable antidepressants, mirtazapine is an attractive option given its tolerability profile, low cost, and wide availability, along with additional potential benefits. Areas covered: The paper provides an overview of the physiology of breathlessness, with an emphasis on central mechanisms, particularly the role of fear circuits and the associated neurotransmitters. It provides a potential rationale for how mirtazapine may improve chronic breathlessness and quality of life in patients with advanced disease. The evidence was identified by a literature search performed in PubMed through to October 2018. Expert opinion: Currently, there is insufficient evidence to support the routine use of antidepressants for chronic breathlessness in advanced disease. Mirtazapine is a promising candidate to pursue, with definitive randomized controlled trials required to determine its efficacy and safety in this setting.

Medication-taking behaviours in young adults with schizophrenia: a pilot study.

The purpose of this prospective and observational study was to explore medication-taking behaviours in community-based young adults with schizophrenia using an electronic monitoring system and patient self-report questionnaires. The Medication Event Monitoring System (MEMS®), the Index for Medication Adherence (IMA) and the Brief Evaluation of Medication Influences and Beliefs (BEMIB) measured medication-taking behaviours. Data were collected at baseline, 4 and 8 weeks. Descriptive statistics were used in analysis. A total of 11 subjects were recruited; one dropped out. Five were male, and five were female. Average age was 32.64 (SD = 5.70) years. Four (40%) were White people; six (60%) were non-White people. The average number of medications treating schizophrenia was 1.9 (SD = 0.57). MEMS® identified 71.77% (SD = 30.47) dose adherence and 55.92% (SD = 31.27) day adherence. Most subjects took medications irregularly (early, late or missing). The BEMIB demonstrated that 50%, 20% and 30% of subjects considered themselves to be adherent to their medications at baseline, 4 weeks and 8 weeks, while the IMA reported 90%, 90% and 80% at baseline, 4 weeks and 8 weeks, respectively. Regarding the observed discrepancies between patients' reports and their actual medication-taking behaviours, clinical implications were discussed. Effective interventions improving medication adherence in schizophrenia are needed for practice and for future studies.

Neural respiratory drive in patients with COPD during exercise tests.

BACKGROUND: It is unknown whether neural drive is comparable in constant rate and incremental exercise tests. Few data have previously been available to address this question because of the lack of reliable methods to assess neural respiratory drive in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVES: The aims of this study are to determine whether neural respiratory drive during constant rate exercise differs from that during incremental exercise and to determine whether neural respiratory drive was maximal at the end of exhaustive exercise tests. METHODS: We studied sixteen patients with moderate-severe COPD (mean ± SD FEV(1) 29 ± 10%). Both diaphragmatic electro-myogram (EMG) and transdiaphragmatic pressure were recorded with a combined multipair electrode balloon catheter during incremental and constant (80% of maximal oxygen consumption derived from a prior incremental exercise test) treadmill exercise. Minute ventilation and oxygen uptake were also measured. RESULTS: Root mean square (RMS) of the diaphragmatic EMG increased gradually without a plateau during incremental exercise, whereas the RMS increased initially and reached a plateau during constant work rate exercise. The RMS of the diaphragmatic EMG at the end of exercise was similar for both incremental and constant work rate exercise (176 ± 42 µV vs. 184 ± 39 µV); these values were 70 and 73% of maximal values recorded over the study. CONCLUSIONS: The pattern of increase in neural respiratory drive during incremental exercise is different to that observed during constant work rate exercise, but both exercise protocols are terminated when the patients achieve a similar but submaximal drive.

Screening for sleep-disordered breathing in neuromuscular disease using a questionnaire for symptoms associated with diaphragm paralysis.

Patients with neuromuscular disease (NMD) are at risk of developing sleep-disordered breathing (SDB) following respiratory muscle involvement. We hypothesised that a questionnaire based on clinical symptoms and signs of diaphragm weakness can be used to screen for SDB in such patients. We developed a self-administered multiple choice questionnaire containing five questions (Sleep-Disordered Breathing in Neuromuscular Disease Questionnaire (SiNQ)-5), scoring 0-10 points. 125 patients were enrolled: 32 with respiratory muscle weakness, 35 subjects with normal respiratory muscle strength and 58 patients with obstructive sleep apnoea (OSA). All subjects underwent full polysomnography. NMD patients with involvement of the respiratory muscles scored mean ± sd 6.8 ± 2.3 out of 10 points, significantly higher than both OSA patients 2.5 ± 2.3 and normal subjects 1.0 ± 2.0 (p < 0.001). A score of five or more points in the SiNQ-5 had a sensitivity of 86.2%, specificity of 88.5%, positive predictive value of 69.4% and a negative predictive value of 95.5% to identify NMD with combined SDB. A short self-administered questionnaire, the SiNQ-5, based on clinical symptoms can reliably screen for SDB in patients with diaphragm weakness. However, comorbidities, such as heart failure, that have symptoms influenced by posture could alter diagnostic accuracy.

Diaphragm electromyogram in infants with abdominal wall defects and congenital diaphragmatic hernia.

Measurement of the diaphragm electromyogram (EMGdi) elicited by phrenic nerve stimulation could be useful to assess neonates suffering from respiratory distress due to diaphragm dysfunction, as observed in infants with abdominal wall defects (AWD) or congenital diaphragmatic hernia (CDH). The study aims were to assess the feasibility of recording EMGdi using a multipair oesophageal electrode catheter and examine whether diaphragm muscle and/or phrenic nerve function was compromised in AWD or CDH infants. Diaphragm compound muscle action potentials elicited by magnetic phrenic nerve stimulation were recorded from 18 infants with surgically repaired AWD (n = 13) or CDH (n = 5), median (range) gestational age 36.5 (34-40) weeks. Diaphragm strength was assessed as twitch transdiaphragmatic pressure (TwP(di)). One AWD patient had prolonged phrenic nerve latency (PNL) bilaterally (left 9.31 ms, right 9.49 ms) and two CDH patients had prolonged PNL on the affected side (10.1 ms and 10.08 ms). There was no difference in left and right TwP(di) in either group. PNL correlated significantly with TwP(di) in CDH (r = 0.8; p = 0.009). Oesophageal EMG and magnetic stimulation of the phrenic nerves can be useful to assess phrenic nerve function in infants. Reduced phrenic nerve conduction accompanies the reduced diaphragm force production observed in infants with CDH.

Acute ischaemic hemispheric stroke is associated with impairment of reflex in addition to voluntary cough.

Cough function is impaired after stroke; this may be important for protection against chest infection. Reflex cough (RC) intensity indices have not been described after stroke. RC, voluntary cough (VC) and respiratory muscle strength were studied in patients within 2 weeks of hemispheric infarct. The null hypotheses were that patients with cortical hemisphere stroke would show the same results as healthy controls on: 1) objective indices of RC and VC intensity; and 2) respiratory muscle strength tests. Peak cough flow rate (PCFR) and gastric pressure (P(ga)) were measured during maximum VC and RC. Participants also underwent volitional and nonvolitional respiratory muscle testing. Nonvolitional expiratory muscle strength was assessed by measuring P(ga) increase after magnetic stimulation over the T10 nerve roots (twitch T10 P(ga)). Stroke severity was scored using the National Institutes of Health Stroke Scale (NIHSS; maximum = 31). 18 patients (mean ± sd age 62 ± 15 yrs and NIHSS score 14 ± 8) and 20 controls (56 ± 16 yrs) participated. VC intensity was impaired in patients (PCFR 287 ± 171 versus 497 ± 122 L·min⁻¹) as was VC P(ga) (98.5 ± 61.6 versus 208.5 ± 61.3 cmH2O; p < 0.001 for both). RC PCFR was reduced in patients (204 ± 111 versus 379 ± 110 L·min⁻¹; p < 0.001), but RC P(ga) was not significantly different from that of controls (179.0 ± 78.0 versus 208.0 ± 77.4 cmH2O; p = 0.266). Patients exhibited impaired volitional respiratory muscle tests, but twitch T10 P(ga) was normal. VC and RC are both impaired in hemispheric stroke patients, despite preserved expiratory muscle strength. Cough coordination is probably cortically modulated and affected by hemispheric stroke.

Neural respiratory drive in obesity.

BACKGROUND: The load imposed on ventilation by increased body mass contributes to the respiratory symptoms caused by obesity. A study was conducted to quantify ventilatory load and respiratory drive in obesity in both the upright and supine postures. METHODS: Resting breathing when seated and supine was studied in 30 obese subjects (mean (SD) body mass index (BMI) 42.8 (8.6) kg/m(2)) and 30 normal subjects (mean (SD) BMI 23.6 (3.7) kg/m(2)), recording the electromyogram of the diaphragm (EMGdi, transoesophageal multipair electrode), gastric and oesophageal pressures. RESULTS: Ventilatory load and neural drive were higher in the obese group as judged by the EMGdi (21.9 (9.0) vs 8.4 (4.0)%max, p<0.001) and oesophageal pressure swings (9.6 (2.9) vs 5.3 (2.2) cm H(2)O, p<0.001). The supine posture caused an increase in oesophageal pressure swings to 16.0 (5.0) cm H(2)O in obese subjects (p<0.001) and to 6.9 (2.0) cm H(2)O in non-obese subjects (p<0.001). The EMGdi increased in the obese group to 24.7 (8.2)%max (p<0.001) but remained the same in non-obese subjects (7.0 (3.4)%max, p = NS). Obese subjects developed intrinsic positive end-expiratory pressure (PEEPi) of 5.3 (3.6) cm H(2)O when supine. Applying continuous positive airway pressure (CPAP) in a subgroup of obese subjects when supine reduced the EMGdi by 40%, inspiratory pressure swings by 25% and largely abolished PEEPi (4.1 (2.7) vs 0.8 (0.4) cm H(2)O, p = 0.009). CONCLUSION: Obese patients have substantially increased neural drive related to BMI and develop PEEPi when supine. CPAP abolishes PEEPi and reduces neural respiratory drive in these patients. These findings highlight the adverse respiratory consequences of obesity and have implications for the clinical management of patients, particularly where the supine posture is required.

Researching breathlessness in palliative care: consensus statement of the National Cancer Research Institute Palliative Care Breathlessness Subgroup.

Breathlessness is common in advanced disease and can have a devastating impact on patients and carers. Research on the management of breathlessness is challenging. There are relatively few studies, and many studies are limited by inadequate power or design. This paper represents a consensus statement of the National Cancer Research Institute Palliative Care Breathlessness Subgroup. The aims of this paper are to facilitate the design of adequately powered multi-centre interventional studies in breathlessness, to suggest a standardised, rational approach to breathlessness research and to aid future 'between study' comparisons. Discussion of the physiology of breathlessness is included.

Neural drive during continuous positive airway pressure (CPAP) and pressure relief CPAP.

BACKGROUND: Pressure release continuous positive airway pressure (CPAP) is an evolution of CPAP that has been reported to improve patient comfort. We hypothesised the pressure release would lead to unloading of the inspiratory muscles and therefore conducted a prospective double-blind cross-over physiological study of autotitrating CPAP (APAP) against autotitrating pressure relief CPAP (PR-APAP). METHODS: Eleven patients with severe obstructive sleep apnoea (OSA; mean AHI 74.5+/-14.4/h) were studied. We assessed neural drive by recording the oesophageal pressure, gastric pressure, transdiaphragmatic pressure and the diaphragm EMG during overnight polysomnography. RESULTS: Both APAP and PR-APAP significantly reduced neural respiratory drive. Transdiaphragmatic pressure swings during apnoea (30.2+/-11.5 cm H2O) before treatment decreased to 9.1+/-5.3 cm H2O for PR-APAP and 8.5+/-3.7 cm H2O for APAP. The transdiaphragmatic pressure and the diaphragm EMG did not differ significantly between APAP and PR-APAP. The gastric pressure swing at expiration phase disappeared during both APAP and PR-APAP when sleep respiratory events were eliminated. CONCLUSIONS: PR-APAP is not superior to APAP in terms of reducing neural respiratory drive. It is unnecessary to replace conventional APAP with PR-APAP for patients who have been successfully treated with traditional APAP.

Ultrasound measurement of rectus femoris cross-sectional area and the relationship with quadriceps strength in COPD.

BACKGROUND: Quadriceps weakness and loss of muscle mass predict mortality in chronic obstructive pulmonary disease (COPD). It was hypothesised that a reduced quadriceps cross-sectional area could be detected by ultrasound in patients with COPD compared with healthy subjects, and that measurements relate to strength and fat-free mass (FFM). METHODS: Rectus femoris muscle cross-sectional area (RF(CSA)) was measured by ultrasound and whole-body FFM estimated using electrical bioimpedance. Quadriceps strength was measured by maximum voluntary contraction and twitch tension (TwQ) following magnetic femoral nerve stimulation. RESULTS: 26 healthy volunteers of mean (SD) age 63 (9) years and 30 patients with COPD of mean (SD) age 67 (9) years and percentage predicted forced expiratory volume in 1 s (FEV(1)) 48.0 (20.8)% with a similar FFM (46.9 (9.3) kg vs 46.1 (7.3) kg, p = 0.193) participated in the study. Mean RF(CSA) was reduced in patients with COPD by 25% of the mean value in healthy subjects(-115 mm(2); 95% CI -177 to -54, p = 0.001) and was related to MRC dyspnoea scale score, independent of FFM or sex. Maximum voluntary contraction strength was linearly related to RF(CSA) in patients with COPD (r = 0.78, p<0.001). TwQ force per unit of RF(CSA) was similar in both healthy individuals and those with COPD (mean (SD) 17 (4) g/mm(2) vs 18 (3) g/mm(2), p = 0.657). Voluntary contraction strength per unit of RF(CSA) was dependent on central quadriceps activation and peripheral oxygen saturation in COPD. CONCLUSION: Ultrasound measurement of RF(CSA) is an effort-independent and radiation-free method of measuring quadriceps muscle cross-sectional area in patients with COPD that relates to strength.

EPR, ENDOR, and special TRIPLE measurements of P(*+) in wild type and modified reaction centers from Rb. sphaeroides.

The influence of the protein environment on the primary electron donor, P, a bacteriochlorophyll a dimer, of reaction centers from Rhodobacter sphaeroides, has been investigated using electron paramagnetic resonance and electron nuclear double resonance spectroscopy. These techniques were used to probe the effects on P that are due to alteration of three amino acid residues, His L168, Asn L170, and Asn M199. The introduction of Glu at L168, Asp at L170, or Asp at M199 changes the oxidation/reduction midpoint potential of P in a pH-dependent manner (Williams et al. (2001) Biochemistry 40, 15403-15407). For the double mutant His L168 to Glu and Asn at L170 to Asp, excitation results in electron transfer along the A-side branch of cofactors at pH 7.2, but at pH 9.5, a long-lived state involving B-side cofactors is produced (Haffa et al. (2004) J Phys Chem B 108, 4-7). Using electron paramagnetic resonance spectroscopy, the mutants with alterations of each of the three individual residues and a double mutant, with changes at L168 and L170, were found to have increased linewidths of 10.1-11.0 G compared to the linewidth of 9.6 G for wild type. The Special TRIPLE spectra were pH dependent, and at pH 8, the introduction of aspartate at L170 increased the spin density ratio, rho (L)/rho (M), to 6.1 while an aspartate at the symmetry related position, M199, decreased the ratio to 0.7 compared to the value of 2.1 for wild type. These results indicate that the energy of the two halves of P changes by about 100 meV due to the mutations and are consistent with the interpretation that electrostatic interactions involving these amino acid residues contribute to the switch in pathway of electron transfer.

Neural respiratory drive in healthy subjects and in COPD.

The aim of the present study was to use the diaphragm electromyogram (EMG(di)) to compare levels of neural respiratory drive (NRD) in a cohort of healthy subjects and chronic obstructive pulmonary disease (COPD) patients, and to investigate the relationship between NRD and pulmonary function in COPD. EMG(di) was recorded at rest and normalised to peak EMG(di) recorded during maximum inspiratory manoeuvres (EMG(di) % max) in 100 healthy subjects and 30 patients with COPD, using a multipair oesophageal electrode. EMG(di) was normalised to the amplitude of the diaphragm compound muscle action potential (CMAP(di,MS)) in 64 healthy subjects. The mean+/-sd EMG(di) % max was 9.0+/-3.4% in healthy subjects and 27.9+/-9.9% in COPD patients, and correlated with percentage predicted forced expiratory volume in one second, vital capacity and inspiratory capacity in patients. EMG(di) % max was higher in healthy subjects aged 51-80 yrs than in those aged 18-50 yrs (11.4+/-3.4 versus 8.2+/-2.9%, respectively). Observations in the healthy group were similar when peak EMG(di) or CMAP(di,MS) were used to normalise EMG(di). Levels of neural respiratory drive were higher in chronic obstructive pulmonary disease patients than healthy subjects, and related to disease severity. Diaphragm compound muscle action potential could be used to normalise diaphragm electromyogram if volitional inspiratory manoeuvres could not be performed, allowing translation of the technique to critically ill and ventilated patients.

A physiological model of patient-reported breathlessness during daily activities in COPD.

Breathlessness during daily activities has a significant impact on quality of life in chronic obstructive pulmonary disease. Herein, we present a physiological model of patient-reported breathlessness based on the relationship between ventilatory load, respiratory muscle capacity, neural respiratory drive and neuromechanical dissociation during daily activities. This model should facilitate an understanding of the mechanisms driving increased intensity of breathlessness during daily activities and the relief of breathlessness following medical or surgical interventions. The model should also provide a structure on which to base the development of patient-reported outcome instruments to measure the severity of breathlessness during daily activities in chronic obstructive pulmonary disease.

Sleep-disordered breathing in unilateral diaphragm paralysis or severe weakness.

Few data exist concerning sleep in patients with hemidiaphragm paralysis or weakness. Traditionally, such patients are considered to sustain normal ventilation in sleep. In the present study, diaphragm strength was measured in order to identify patients with unilateral paralysis or severe weakness. Patients underwent polysomnography with additional recordings of the transoesophageal electromyogram (EMG) of the diaphragm and surface EMG of extra-diaphragmatic respiratory muscles. These data were compared with 11 normal, healthy subjects matched for sex, age and body mass index (BMI). In total, 11 patients (six males, mean+/-sd age 56.5+/-10.0 yrs, BMI 28.7+/-2.8 kg x m(-2)) with hemidiaphragm paralysis or severe weakness (unilateral twitch transdiaphragmatic pressure 3.3+/-1.7 cmH(2)O (0.33+/-0.17 kPa) were studied. They had a mean+/-sd respiratory disturbance index of 8.1+/-10.1 events x h(-1) during non-rapid eye movement (NREM) sleep and 26.0+/-17.8 events x h(-1) during rapid eye movement (REM) sleep (control groups 0.4+/-0.4 and 0.7+/-0.9 events x h(-1), respectively). The diaphragm EMG, as a percentage of maximum, was double that of the control group in NREM sleep (15.3+/-5.3 versus 8.9+/-4.9% max, respectively) and increased in REM sleep (20.0+/-6.9% max), while normal subjects sustained the same level of activation (6.2+/-3.1% max). Patients with unilateral diaphragm dysfunction are at risk of developing sleep-disordered breathing during rapid eye movement sleep. The diaphragm electromyogram, reflecting neural respiratory drive, is doubled in patients compared with normal subjects, and increases further in rapid eye movement sleep.

Neural respiratory drive during apnoeic events in obstructive sleep apnoea.

For a given neural drive, oesophageal pressure during apnoeic episodes may differ from that during airflow, since inspiratory airflow and increased lung volume both reduce pressure generation. It was, therefore, hypothesised that diaphragm electromyography (EMG) may provide additional data to oesophageal pressure when used for the assessment of neural drive in patients with obstructive sleep apnoea, whose breathing is associated with variable airflow and changes in lung volume. Neural respiratory drive was assessed using diaphragm EMG recorded from multipair oesophageal electrodes in 12 patients with obstructive sleep apnoea. Oesophageal pressure was also recorded. The mean+/-sd inspiratory oesophageal pressure swing was 11.0+/-3.7 cmH(2)O during wakefulness, 38.2+/-15.7 cmH(2)O at the end of the apnoea and reduced to 28.5+/-10.4 cmH(2)O at the beginning of arousal. The mean peak inspiratory diaphragm EMG signal was 21.8+/-6.5 muV during wakefulness, 38.6+/-14.0 muV at the end of the apnoea and further increased to 59.6+/-32.0 muV at the beginning of arousal. It was concluded that the pattern of neural drive assessed by oesophageal pressure differs from that measured by diaphragm electromyography during apnoeic events and, therefore, that diaphragm electromyography may be a useful adjunct to measurement of oesophageal pressure for the assessment of neural drive in patients with obstructive sleep apnoea.

Intraoperative endoscopy in a child with Turner's syndrome and gastrointestinal hemorrhage: a case report.

Gastrointestinal bleeding in Turner's syndrome can represent vascular lesions that are frequently beyond standard endoscopic reach and often life threatening. This report describes the successful use of intraoperative endoscopy to identify the souce of bleeding in an adolescent with Turner's syndrome and significant intestinal hemorrhage. J Pediatr Surg 36:951-952.

Induction of bile acid synthesis by cholesterol and cholestyramine feeding is unimpaired in mice deficient in apolipoprotein AI.

High density lipoprotein (HDL) cholesterol is believed to be preferentially utilized for bile acid synthesis and biliary secretion. In mice, the deletion of apolipoprotein AI (apo AI), the major apolipoprotein in HDL, results in very low plasma HDL-cholesterol levels. This article describes bile acid metabolism in apo AI-deficient (Apo AI(-/-)) mice and their C57BL/6 (Apo AI(+/+)) controls fed either a basal rodent diet alone or containing cholesterol or cholestyramine. Basal plasma HDL-cholesterol levels in the (-/-) mice (<10 mg/dL) were less than 20% of those in their (+/+) controls, but there were no phenotypic differences in either the relative cholesterol content of gallbladder bile, bile acid pool size and composition, fecal bile acid excretion or the activity of, or mRNA level for, cholesterol 7alpha-hydroxylase. However, compared with their (+/+) controls, the (-/-) mice absorbed more cholesterol (33 vs. 24%) and manifested lower rates of hepatic sterol synthesis (534 vs. 1,019 nmol/h per g). Cholesterol feeding increased hepatic cholesterol levels in the (+/+) animals from 2.7 to 4.4 mg/g and in the (-/-) mice from 2.6 to 8.1 mg/g. Bile acid synthesis increased 70% in both genotypes. Cholestyramine feeding stimulated bile acid synthesis 3.7 fold in both (-/-) and (+/+) mice. We conclude that the virtual loss of HDL-cholesterol from the circulation in apo AI deficiency has no impact on the ability of the hepatocyte to adapt its rate of bile acid synthesis in concert with the amount of cholesterol and bile acid returning to the liver from the small intestine.

Nitric oxide synthase activity and expression in experimental diabetic neuropathy.

The changes of nitric oxide synthase (NOS) activity and expression in experimental diabetic neuropathy have not been examined. Increases in ganglia NOS might be similar to those that follow axotomy, whereas declines in endothelial NOS (eNOS) and immunological NOS (iNOS) might explain dysfunction of microvessels or macrophages. In this work, we studied NOS activity in lumbar dorsal root ganglia (DRG) of rats with both short- and long-term experimental streptozotocin-induced diabetes and correlated it with expression of each of the 3 NOS isoforms. NOS enzymatic activity in DRG increased after 12 months of diabetes. This increase, however, was not accompanied by an increase in neuronal NOS immunohistochemistry or mRNA. Immunohistochemical and RT-PCR studies did not identify changes of eNOS expression in 12-month sciatic nerves or DRG from diabetics. Two-month diabetic DRG had increased eNOS mRNA and there was novel eNOS labeling of capsular DRG and perineurial cells. iNOS mRNA levels were lower in diabetics at both time points in peripheral nerves but were unchanged in DRG. Diabetic ganglia showed an increase in NOS activity not explained by novel NOS isoform synthesis. The increases may compensate for NO "quenching" by endproducts of glycosylation. Declines in iNOS may indicate impaired macrophage function.