Pharmacokinetic interaction between verapamil and ritonavir-boosted nirmatrelvir: implications for the management of COVID-19 in patients with hypertension.

A woman in her 80s was brought to the emergency department for acute onset of generalised weakness, lethargy and altered mental state. The emergency medical service found her to have symptomatic bradycardia, and transcutaneous pacing was done. Medical history was notable for hypertension, hyperlipidaemia, type 2 diabetes, and a recently diagnosed SARS-CoV-2 (COVID-19) infection for which she was prescribed ritonavir-boosted nirmatrelvir (Paxlovid) two days before the presentation. On arrival at the hospital, she was found to have marked bradycardia with widened QRS, hyperglycaemia and metabolic acidosis. Transvenous pacing along with pressor support and insulin were initiated, and she was admitted to the intensive care unit. Drug interaction between ritonavir-boosted nirmatrelvir and verapamil leading to verapamil toxicity was suspected of causing her symptoms, and both drugs were withheld. She reverted to sinus rhythm on the fourth day, and the pacemaker was discontinued.

Simultaneous kidney and pancreas transplantation in a patient with nail-patella syndrome and insulin-dependent diabetes.

BACKGROUND: Nail-patella syndrome (NPS) is a rare autosomal dominant disorder caused by a mutation in LIM-homeodomain transcription factor 1-beta (LMX1B) and characterized by nail dystrophy, skeletal changes, glaucoma, and kidney disease with up to 30% of patients progressing to kidney failure. Autoimmune diseases, including thyroid disease, have been reported previously in patients with NPS. CASE-DIAGNOSIS/TREATMENT: We report the case of a pediatric patient with NPS with kidney failure, hypothyroidism, and type 1 diabetes mellitus. The patient's pedigree and identification of a kidney specific mutation in LMX1B was a result of whole exome sequencing. Clinical data was obtained from retrospective chart review and included the 1-year post-transplant follow-up period. At 15 years of age, our patient received a simultaneous kidney-pancreas transplantation, from a 3 HLA antigen mismatched deceased donor. The donor was CMV + , EBV - and our patient was CMV - , EBV - at time of transplant. Our patient maintained normal kidney function and euglycemia without insulin therapy at 1 year post-transplant. CONCLUSIONS: The patient's hypothyroidism, diabetes mellitus, and kidney failure may all be related to LMX1B mutation. Further study is needed to clarify the genetic link between these processes. Simultaneous kidney-pancreas transplantation can be used to successfully treat diabetes mellitus and kidney failure in a pediatric patient.

Comparison of recidivism rates for a teenage trauma prevention program after the addition of high-fidelity patient simulation.

OBJECTIVES: We evaluated the benefits of adding high-fidelity simulation to a teenage trauma prevention program to decrease recidivism rates and encourage teens to discuss actionable steps toward safe driving. METHODS: A simulated pediatric trauma scenario was integrated into an established trauma prevention program. Participants were recruited because they were court-ordered to attend this program after misdemeanor convictions for moving violations. The teenage participants viewed this simulation from the emergency medical services (EMS) handoff to complete trauma care. Participants completed a postsimulation knowledge assessment and care evaluation, which included narrative data about the experience. Qualitative analysis of color-coded responses identified common themes and experiences in participants' answers. Court records were reviewed 6 years after course completion to determine short- and long-term recidivism rates, which were then compared to our program's historical rate. RESULTS: One hundred twenty-four students aged 16-20 years participated over a 2-year study period. Narrative responses included general reflection, impressions, and thoughts about what they might change as a result of the course. Participants reported that they would decrease speed (30%), wear seat belts (15%), decrease cell phone use (11%), and increase caution (28%). The recidivism rate was 55% within 6 years. At 6 months it was 8.4%, at 1 year it was 20%, and it increased approximately 5-8% per year after the first year. Compared with our programs, for historical 6-month and 2-year recidivism rates, no significant difference was seen with or without simulation. CONCLUSIONS: Adding simulation is well received by participants and leads to positive reflections regarding changes in risk-taking behaviors but resulted in no changes to the high recidivism rates This may be due to the often ineffectiveness of fear appeals.

Roflumilast reverses CFTR-mediated ion transport dysfunction in cigarette smoke-exposed mice.

BACKGROUND: Dysfunction in cystic fibrosis transmembrane conductance regulator (CFTR) can be elicited by cigarette smoke and is observed in patients with chronic bronchitis. We have previously demonstrated in human airway epithelial cell monolayers that roflumilast, a clinically approved phosphodiesterase 4 inhibitor that reduces the risk of exacerbations in chronic obstructive pulmonary disease patients with chronic bronchitis and a history of exacerbations, activates CFTR-dependent chloride secretion via a cAMP-mediated pathway, partially restores the detrimental effects of cigarette smoke on CFTR-mediated ion transport, and increases CFTR-dependent gastrointestinal fluid secretion in isolated murine intestine segments. Based on these findings, we hypothesized that roflumilast could improve CFTR-mediated chloride transport and induce secretory diarrhea in mice exhibiting cigarette smoke-induced CFTR dysfunction. METHODS: A/J mice expressing wild type CFTR (+/+) were exposed to cigarette smoke or air with or without roflumilast and the effect of treatment on CFTR-dependent chloride transport was quantified using nasal potential difference (NPD) measurements in vivo and short-circuit current (Isc) analysis of trachea ex vivo. Stool specimen were collected and the wet/dry ratio measured to assess the effect of roflumilast on secretory diarrhea. RESULTS: Acute roflumilast treatment increased CFTR-dependent chloride transport in both smoke- and air-exposed mice (smoke, -2.0 ± 0.4 mV, 131.3 ± 29.3 µA/cm2, P < 0.01 and air, 3.9 ± 0.8 mV, 147.7 ± 38.0 µA/cm2, P < 0.01 vs. vehicle -0.3 ± 0.7 mV, 10.4 ± 7.0 µA/cm2). Oral administration of roflumilast over five weeks completely reversed the deleterious effects of cigarette smoke on CFTR function in smoke-exposed animals, in which CFTR-dependent chloride transport was 64% that of air controls (roflumilast, -15.22 ± 2.7 mV vs. air, -14.45 ± 1.4 mV, P < 0.05). Smoke exposure increased the wet/dry ratio of stool specimen to a level beyond which roflumilast had little additional effect. CONCLUSIONS: Roflumilast effectively rescues CFTR-mediated chloride transport in vivo, further implicating CFTR activation as a mechanism through which roflumilast benefits patients with bronchitis.

Pediatric anaphylaxis in the operating room for anesthesia residents: a simulation study.

BACKGROUND: Pediatric intraoperative emergencies are rare but it is crucial for an anesthesia resident to be proficient in their management. Even the more common emergencies like anaphylaxis may not happen frequently for this proficiency to occur. Simulation increases exposure to these rare events in a safe learning environment to improve skills and build confidence while standardizing curriculum. OBJECTIVE: Anesthesia residents participated in a simulated case of intraoperative pediatric anaphylaxis to evaluate knowledge and performance gaps. The study also sought to determine whether a difference exists between second- (CA2) and third-year (CA3) anesthesia residents when managing pediatric anaphylaxis and cardiopulmonary arrest. METHODS: Anesthesia residents completed a standardized programmed simulation of intraoperative anaphylaxis in a 5-year old undergoing tonsillectomy and adenoidectomy. Anaphylaxis presented and progressed to bradycardia and pulseless electrical activity if anaphylaxis went unnoticed or untreated. Key time points were recorded. A scripted debriefing and written evaluation followed. RESULTS: Average time to diagnose anaphylaxis was 7.6 min, and time to give epinephrine was 6.5 min. Thirty-five percent of residents started epinephrine infusion following initial bolus. Average time calling for help between CA3 and CA2 residents was 2.5 min vs 5 min (P = 0.01). CA3 residents verbalized a broader differential, including malignant hyperthermia and pneumothorax. Progression to pulseless electrical activity occurred in 65% of sessions prior to epinephrine being administered. No resident initiated chest compressions for bradycardia. CONCLUSIONS: Important performance deficits were seen in senior anesthesia residents during a simulated case of pediatric intraoperative anaphylaxis. Although CA3 performed better, deficits still existed. Anesthesia residents and training programs should partner in developing additional training recognizing anaphylaxis, pulseless electrical activity, and indication for chest compressions in a child.

The Cystic Fibrosis Transmembrane Conductance Regulator Potentiator Ivacaftor Augments Mucociliary Clearance Abrogating Cystic Fibrosis Transmembrane Conductance Regulator Inhibition by Cigarette Smoke.

Acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction may contribute to chronic obstructive pulmonary disease pathogenesis and is a potential therapeutic target. We sought to determine the acute effects of cigarette smoke on ion transport and the mucociliary transport apparatus, their mechanistic basis, and whether deleterious effects could be reversed with the CFTR potentiator ivacaftor (VX-770). Primary human bronchial epithelial (HBE) cells and human bronchi were exposed to cigarette smoke extract (CSE) and/or ivacaftor. CFTR function and expression were measured in Ussing chambers and by surface biotinylation. CSE-derived acrolein modifications on CFTR were determined by mass spectroscopic analysis of purified protein, and the functional microanatomy of the airway epithelia was measured by 1-µm resolution optical coherence tomography. CSE reduced CFTR-dependent current in HBE cells (P < 0.05) and human bronchi (P < 0.05) within minutes of exposure. The mechanism involved CSE-induced reduction of CFTR gating, decreasing CFTR open-channel probability by approximately 75% immediately after exposure (P < 0.05), whereas surface CFTR expression was partially reduced with chronic exposure, but was stable acutely. CSE treatment of purified CFTR resulted in acrolein modifications on lysine and cysteine residues that likely disrupt CFTR gating. In primary HBE cells, CSE reduced airway surface liquid depth (P < 0.05) and ciliary beat frequency (P < 0.05) within 60 minutes that was restored by coadministration with ivacaftor (P < 0.005). Cigarette smoking transmits acute reductions in CFTR activity, adversely affecting the airway surface. These effects are reversible by a CFTR potentiator in vitro, representing a potential therapeutic strategy in patients with chronic obstructive pulmonary disease with chronic bronchitis.

Combination therapy with cystic fibrosis transmembrane conductance regulator modulators augment the airway functional microanatomy.

Recently approved therapies that modulate CFTR function have shown significant clinical benefit, but recent investigations regarding their molecular mechanism when used in combination have not been consistent with clinical results. We employed micro-optical coherence tomography as a novel means to assess the mechanism of action of CFTR modulators, focusing on the effects on mucociliary clearance. Primary human airway monolayers from patients with a G551D mutation responded to ivacaftor treatment with increased ion transport, airway surface liquid depth, ciliary beat frequency, and mucociliary transport rate, in addition to decreased effective viscosity of the mucus layer, a unique mechanism established by our findings. These endpoints are consistent with the benefit observed in G551D patients treated with ivacaftor, and identify a novel mechanism involving mucus viscosity. In monolayers derived from F508del patients, the situation is more complicated, compounded by disparate effects on CFTR expression and function. However, by combining ion transport measurements with functional imaging, we establish a crucial link between in vitro data and clinical benefit, a finding not explained by ion transport studies alone. We establish that F508del cells exhibit increased mucociliary transport and decreased mucus effective viscosity, but only when ivacaftor is added to the regimen. We further show that improvement in the functional microanatomy in vitro corresponds with lung function benefit observed in the clinical trials, whereas ion transport in vitro corresponds to changes in sweat chloride. Functional imaging reveals insights into clinical efficacy and CFTR biology that significantly impact our understanding of novel therapies.

Catheter-Directed Low-Dose Tissue Plasminogen Activator for Treatment of Right Atrial Thrombus Caused by a Central Venous Catheter.

Catheter-related atrial thrombosis is a potentially deadly complication of central venous catheters. Options for treatment include surgical thrombectomy, systemic anticoagulation, and systemic thrombolysis, but the optimal method of treatment remains unknown. We describe a 48-year-old woman with a large right atrial thrombus who was successfully treated with localized recombinant tissue plasminogen activator (tPA). She was treated with an 18-hour infusion of localized low-dose tPA administered through her central venous catheter. The dimensions of the thrombus decreased from 30 × 16 × 22 mm to 10 × 8 × 5 mm after treatment with tPA, corresponding to an associated 96% reduction in thrombus volume. No major bleeding complications were observed. Catheter-directed thrombolysis provides the theoretical advantage of a decreased rate of major bleeding by reducing the exposure to and duration of high-dose systemic thrombolytic therapy. To our knowledge, this is the second case report describing the use of this novel therapy. Although no guidelines for the treatment of atrial thrombosis or consensus on the optimal regimen for catheter-directed thrombolysis (and intensity of concomitant anticoagulation) exist, we believe that this intervention may be a well-tolerated alternative to systemic thrombolysis and surgery in certain patients.

Evaluation of pure ground glass pulmonary nodule: a case report.

A pulmonary nodule is a single, nearly spherical, well-circumscribed pulmonary opacity up to 30 mm in diameter and surrounded by aerated lung tissue. In radiographs, pulmonary nodules may appear as solid, completely obscuring the lung parenchyma, or as subsolid, not completely obscuring adjacent tissues. A subsolid pulmonary nodule may be further subclassified as a pure ground glass nodule (pGGN) or a part solid nodule, a mixture of ground glass components and focal opacity obscuring the adjacent tissues. Guidelines for evaluation of solid pulmonary nodules are based on nodule size, recommending vigilance and non-operative management for small nodules (less than 8 mm in diameter) and diagnostic biopsy for nodules with a diameter of 8 mm or more. However, subsolid ground glass pulmonary nodules are an exception to this rule. Although small in size, persistent subsolid nodules are potentially premalignant or malignant. We present the case of a non-smoker who was found to have an incidental pulmonary pGGN. We then discuss the radiologic appearance, histology, clinical outcomes, and evaluation and management strategy of subsolid pulmonary nodules compared with solid nodules.

Cigarette smoke induces systemic defects in cystic fibrosis transmembrane conductance regulator function.

RATIONALE: Several extrapulmonary disorders have been linked to cigarette smoking. Smoking is reported to cause cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in the airway, and is also associated with pancreatitis, male infertility, and cachexia, features characteristic of cystic fibrosis and suggestive of an etiological role for CFTR. OBJECTIVES: To study the effect of cigarette smoke on extrapulmonary CFTR function. METHODS: Demographics, spirometry, exercise tolerance, symptom questionnaires, CFTR genetics, and sweat chloride analysis were obtained in smokers with and without chronic obstructive pulmonary disease (COPD). CFTR activity was measured by nasal potential difference in mice and by Ussing chamber electrophysiology in vitro. Serum acrolein levels were estimated with mass spectroscopy. MEASUREMENTS AND MAIN RESULTS: Healthy smokers (29.45 ± 13.90 mEq), smokers with COPD (31.89 ± 13.9 mEq), and former smokers with COPD (25.07 ± 10.92 mEq) had elevated sweat chloride levels compared with normal control subjects (14.5 ± 7.77 mEq), indicating reduced CFTR activity in a nonrespiratory organ. Intestinal current measurements also demonstrated a 65% decrease in CFTR function in smokers compared with never smokers. CFTR activity was decreased by 68% in normal human bronchial epithelial cells exposed to plasma from smokers, suggesting that one or more circulating agents could confer CFTR dysfunction. Cigarette smoke-exposed mice had decreased CFTR activity in intestinal epithelium (84.3 and 45%, after 5 and 17 wk, respectively). Acrolein, a component of cigarette smoke, was higher in smokers, blocked CFTR by inhibiting channel gating, and was attenuated by antioxidant N-acetylcysteine, a known scavenger of acrolein. CONCLUSIONS: Smoking causes systemic CFTR dysfunction. Acrolein present in cigarette smoke mediates CFTR defects in extrapulmonary tissues in smokers.

A case of apical ballooning syndrome in a male with status asthmaticus; highlighting the role of B2 agonists in the pathophysiology of a reversible cardiomyopathy.

Apical ballooning syndrome (ABS), also known as Takotsubo cardiomyopathy, was first reported by Dote and colleagues in Japanese literature in 1991 in a review of five cases. Case series have highlighted the association of severe psychological stressors as the major precipitating factors of this syndrome. Status Epilepticus and Sub-Arachnoid hemorrhage are also now established independent etiologies for this phenomenon in patients without coronary artery disease. We report a case of reversible apical ventricular dysfunction in a 50-year-old male presenting with status asthmaticus who quickly underwent intubation. Following this, he had ST elevations in precordial leads with mild cardiac enzyme leak. Subsequent cardiac catheterization revealed a left ventricular ejection fraction of 25-30% with apical aneurismal segment. No obstructive disease was observed. Three days later there was marked clinical improvement; the patient was extubated and repeat echocardiography revealed a remarkable return to normal ventricular size and systolic function. Our case demonstrates that excess use of beta-agonists may be a potential risk factor for ABS and raises the possibility of cathecholamine cardiotoxicity being mediated via beta-receptors. Furthermore, it also negates the propensity of apical ballooning so far reported only in women with respiratory distress without confounding emotional stressors.

Work-related health risks in Europe: are older workers more vulnerable?

Recent policy reforms in a number of countries are extending working lives and deferring the statutory retirement age. Yet such changes may have profound implications for the well-being of older workers if such individuals are more likely to suffer work-related health problems. Using international data from the European Working Conditions Survey for 2005, we test whether older workers (aged 55-65 years) differ significantly from younger workers across a range of self-reported job-related indicators including health risk perception, mental and physical health, sickness absence, injury and fatigue. We estimate discrete choice (probit) models of the outcomes above for a sample comprising 17,459 individuals in 23 countries, and control for personal, job and work characteristics including exposure to physical, ergonomic and psychosocial risk factors. Our results show that failure to account for both endogeneity and the 'healthy worker effect' (sample selection) can lead to misleading inferences. The latter is especially important: only after controlling for selection bias (using a re-weighting approach) do we find older workers are more 'vulnerable' than their younger counterparts in the sense of being significantly more likely to perceive each of the various adverse health outcomes above, with the exception of injury. For the remaining indicators, our estimates suggest the magnitude of this difference is substantial: between 5 and 11 percentage points compared with prime age workers, and 8 and 14 points relative to workers aged 15-35, depending on the measure under consideration.

A pharmacologic approach to acquired cystic fibrosis transmembrane conductance regulator dysfunction in smoking related lung disease.

BACKGROUND: Mucus stasis in chronic obstructive pulmonary disease (COPD) is a significant contributor to morbidity and mortality. Potentiators of cystic fibrosis transmembrane conductance regulator (CFTR) activity pharmacologically enhance CFTR function; ivacaftor is one such agent approved to treat CF patients with the G551D-CFTR gating mutation. CFTR potentiators may also be useful for other diseases of mucus stasis, including COPD. METHODS AND FINDINGS: In primary human bronchial epithelial cells, exposure to cigarette smoke extract diminished CFTR-mediated anion transport (65.8±0.2% of control, P<0.005) and mucociliary transport (0.17±0.05 µm/sec vs. 2.4±0.47 µm/sec control, P<0.05) by reducing airway surface liquid depth (7.3±0.6 µm vs. 13.0±0.6 µm control, P<0.005) and augmenting mucus expression (by 64%, P<0.05) without altering transepithelial resistance. Smokers with or without COPD had reduced CFTR activity measured by nasal potential difference compared to age-matched non-smokers (-6.3±1.4 and -8.0±2.0 mV, respectively vs. -15.2±2.7 mV control, each P<0.005, n = 12-14/group); this CFTR decrement was associated with symptoms of chronic bronchitis as measured by the Breathlessness Cough and Sputum Score (r = 0.30, P<0.05) despite controlling for smoking (r = 0.31, P<0.05). Ivacaftor activated CFTR-dependent chloride transport in non-CF epithelia and ameliorated the functional CFTR defect induced by smoke to 185±36% of non-CF control (P<0.05), thereby increasing airway surface liquid (from 7.3±0.6 µm to 10.1±0.4 µm, P<0.005) and mucociliary transport (from 0.27±0.11 µm/s to 2.7±0.28 µm/s, P<0.005). CONCLUSIONS: Cigarette smoking reduces CFTR activity and is causally related to reduced mucus transport in smokers due to inhibition of CFTR dependent fluid transport. These effects are reversible by the CFTR potentiator ivacaftor, representing a potential therapeutic strategy to augment mucociliary clearance in patients with smoking related lung disease.

Suppression of CFTR premature termination codons and rescue of CFTR protein and function by the synthetic aminoglycoside NB54.

Certain aminoglycosides are capable of inducing "translational readthrough" of premature termination codons (PTCs). However, toxicity and relative lack of efficacy deter treatment with clinically available aminoglycosides for genetic diseases caused by PTCs, including cystic fibrosis (CF). Using a structure-based approach, the novel aminoglycoside NB54 was developed that exhibits reduced toxicity and enhanced suppression of PTCs in cell-based reporter assays relative to gentamicin. We examined whether NB54 administration rescued CFTR protein and function in clinically relevant CF models. In a fluorescence-based halide efflux assay, NB54 partially restored halide efflux in a CF bronchial epithelial cell line (CFTR genotype W1282X/F508del), but not in a CF epithelial cell line lacking a PTC (F508del/F508del). In polarized airway epithelial cells expressing either a CFTR-W1282X or -G542X cDNA, treatment with NB54 increased stimulated short-circuit current (I (SC)) with greater efficiency than gentamicin. NB54 and gentamicin induced comparable increases in forskolin-stimulated I (SC) in primary airway epithelial cells derived from a G542X/F508del CF donor. Systemic administration of NB54 to Cftr-/- mice expressing a human CFTR-G542X transgene restored 15-17% of the average stimulated transepithelial chloride currents observed in wild-type (Cftr+/+) mice, comparable to gentamicin. NB54 exhibited reduced cellular toxicity in vitro and was tolerated at higher concentrations than gentamicin in vivo. These results provide evidence that synthetic aminoglycosides are capable of PTC suppression in relevant human CF cells and a CF animal model and support further development of these compounds as a treatment modality for genetic diseases caused by PTCs.

Platelet production and platelet destruction: assessing mechanisms of treatment effect in immune thrombocytopenia.

This study investigated the immature platelet fraction (IPF) in assessing treatment effects in immune thrombocytopenia (ITP). IPF was measured on the Sysmex XE2100 autoanalyzer. The mean absolute-IPF (A-IPF) was lower for ITP patients than for healthy controls (3.2 vs 7.8 × 109/L, P < .01), whereas IPF percentage was greater (29.2% vs 3.2%, P < .01). All 5 patients with a platelet response to Eltrombopag, a thrombopoietic agent, but none responding to an anti-FcγRIII antibody, had corresponding A-IPF responses. Seven of 7 patients responding to RhoD immuneglobulin (anti-D) and 6 of 8 responding to intravenous immunoglobulin (IVIG) did not have corresponding increases in A-IPF, but 2 with IVIG and 1 with IVIG anti-D did. This supports inhibition of platelet destruction as the primary mechanism of intravenous anti-D and IVIG, although IVIG may also enhance thrombopoiesis. Plasma glycocalicin, released during platelet destruction, normalized as glycocalicin index, was higher in ITP patients than controls (31.36 vs 1.75, P = .001). There was an inverse correlation between glycocalicin index and A-IPF in ITP patients (r² = -0.578, P = .015), demonstrating the relationship between platelet production and destruction. Nonresponders to thrombopoietic agents had increased megakaryocytes but not increased A-IPF, suggesting that antibodies blocked platelet release. In conclusion, A-IPF measures real-time thrombopoiesis, providing insight into mechanisms of treatment effect.

Cystic fibrosis transmembrane conductance regulator protein repair as a therapeutic strategy in cystic fibrosis.

PURPOSE OF REVIEW: Recent progress in understanding the production, processing, and function of the cystic fibrosis gene product, the cystic fibrosis transmembrane conductance regulator (CFTR), has revealed new therapeutic targets to repair the mutant protein. Classification of CFTR mutations and new treatment strategies to address each will be described here. RECENT FINDINGS: High-throughput screening and other drug discovery efforts have identified small molecules that restore activity to mutant CFTR. Compounds such as VX-770 that potentiate CFTR have demonstrated exciting results in recent clinical trials and demonstrate robust effects across several CFTR mutation classes in the laboratory. A number of novel F508del CFTR processing correctors restore protein to the cell surface and improve ion channel function in vitro and are augmented by coadministration of CFTR potentiators. Ongoing discovery efforts that target protein folding, CFTR trafficking, and cell stress have also indicated promising results. Aminoglycosides and the novel small molecule ataluren induce translational readthrough of nonsense mutations in CFTR and other genetic diseases in vitro and in vivo and have shown activity in proof of concept trials, and ataluren is now being studied in confirmatory trials. SUMMARY: An improved understanding of the molecular mechanisms underlying the basic genetic defect in cystic fibrosis have led to new treatment strategies to repair the mutant protein.

Activation of the cystic fibrosis transmembrane conductance regulator by the flavonoid quercetin: potential use as a biomarker of ΔF508 cystic fibrosis transmembrane conductance regulator rescue.

Therapies to correct the ΔF508 cystic fibrosis transmembrane conductance regulator (CFTR) folding defect require sensitive methods to detect channel activity in vivo. The ß2 adrenergic receptor agonists, which provide the CFTR stimuli commonly used in nasal potential difference assays, may not overcome the channel gating defects seen in ΔF508 CFTR after plasma membrane localization. In this study, we identify an agent, quercetin, that enhances the detection of surface ΔF508 CFTR, and is suitable for nasal perfusion. A screen of flavonoids in CFBE41o⁻ cells stably transduced with ΔF508 CFTR, corrected to the cell surface with low temperature growth, revealed that quercetin stimulated an increase in the short-circuit current. This increase was dose-dependent in both Fisher rat thyroid and CFBE41o⁻ cells. High concentrations inhibited Cl⁻ conductance. In CFBE41o⁻ airway cells, quercetin (20 µg/ml) activated ΔF508 CFTR, whereas the ß2 adrenergic receptor agonist isoproterenol did not. Quercetin had limited effects on cAMP levels, but did not produce detectable phosphorylation of the isolated CFTR R-domain, suggesting an activation independent of channel phosphorylation. When perfused in the nares of Cftr(+) mice, quercetin (20 µg/ml) produced a hyperpolarization of the potential difference that was absent in Cftr(-/-) mice. Finally, quercetin-induced, dose-dependent hyperpolarization of the nasal potential difference was also seen in normal human subjects. Quercetin activates CFTR-mediated anion transport in respiratory epithelia in vitro and in vivo, and may be useful in studies intended to detect the rescue of ΔF508 CFTR by nasal potential difference.

Epidemiology of spine trauma in an Irish regional trauma unit: a 4-year study.

Currently there is a lack of information on the full spectrum of spine trauma presenting to medical services in a defined geographic area. This study analyses the aetiology and demographics of a cohort of spine trauma in the West of Ireland. A regional trauma unit has been investigated for a 51-month period. Two hundred and eighty-five cases admitted with spine trauma were documented. The annual incidence of traumatic spinal injury was 19.54 cases/100,000 persons per year. Falls and low-energy trauma are shown to constitute a significant proportion of all cases (60.35%). Injury at greater than one level is frequently present. The highest peak of injury occurred in the 20-24-year-old age group (11.58%). A second peak occurred at 75-79 years of age (7.37%). The commonest cause of neurological injury was falls (n=9; 64.3%). This spine trauma register has provided valuable insights into the patterns of injury encountered in spine trauma patients in this region. It may act as a blueprint for a national spine trauma register and highlights the importance of patient education and injury prevention strategies.

Effects of off-pump coronary artery bypass grafting on patient outcome.

BACKGROUND: Cardiopulmonary bypass (CPB) is associated with postoperative myocardial stunning, hypothermia, formation of microemboli, and systemic inflammatory response syndrome, all of which may prolong recovery from coronary artery bypass grafting (CABG) surgery. This study sought to compare outcomes in patients undergoing CABG off pump versus on pump. METHODS: Outcomes, including mortality and several morbidities, were reviewed in 1,623 on-pump patients and 683 off-pump patients. Morbidities assessed included postoperative bleeding, incidence of multiorgan dysfunction, and neurologic complications. Chi-square and t-test analysis were used to determine statistical significance. RESULTS: Mortality was 42% lower in the off-pump group than the on-pump group. Both critical care and total hospital length of stay were significantly shorter in the off-pump group. The incidence of postoperative bleeding requiring transfusion or a return to the operating room was reduced by 29% in the off-pump group and the incidence of multiorgan dysfunction was reduced by 31%. The off-pump patients also presented a significantly lower incidence of cerebral vascular accidents and seizures than on-pump patients. CONCLUSIONS: We conclude that there is an association between improved patient outcome and off-pump CABG surgery. The outcomes of this study show a statistically significant decrease in mortality, critical care length of stay, total hospital stay, incidence of bleeding requiring transfusion or return to the operating room, amount of blood transfused, incidence of multiorgan dysfunction, cerebral vascular accidents, and seizures in off-pump patients when compared with on-pump patients. Such results support the use of myocardial revascularization off pump as an alternative to CABG surgery on pump. CABG surgery off pump may allow a better postoperative clinical course in patients who are candidates for the procedure.