Impact of CLAD Phenotype on Survival After Lung Retransplantation: A Multicenter Study.

Chronic lung allograft dysfunction (CLAD) remains a major problem after lung transplantation with no definitive treatment except redo lung transplantation (re-LTx) in selected candidates. However, CLAD is not a homogeneous entity and different phenotypes exist. Therefore, we aimed to evaluate the effect of CLAD phenotypes on survival after re-LTx for CLAD. Patients who underwent re-LTx for respiratory failure secondary to CLAD in four LTx centers between 2003 and 2013 were included in this retrospective analysis. Bronchiolitis obliterans syndrome (BOS) and restrictive CLAD (rCLAD) were distinguished using pulmonary function, radiology and explant lung histopathology. Patient variables pre- and post-re-LTx were collected and analyzed. A total of 143 patients underwent re-LTx for CLAD resulting in 94 BOS (66%) and 49 rCLAD (34%) patients. Unadjusted and adjusted survival after re-LTx for rCLAD was worse compared to BOS (HR = 2.60, 1.59-4.24; p < 0.0001 and HR = 2.61, 1.51-4.51; p = 0.0006, respectively). Patients waiting at home prior to re-LTx experienced better survival compared to hospitalized patients (HR 0.40; 0.23-0.72; p = 0.0022). Patients with rCLAD redeveloped CLAD earlier and were more likely to redevelop rCLAD. Survival after re-LTx for rCLAD is worse compared to BOS. Consequently, re-LTx for rCLAD should be critically discussed, particularly when additional peri-operative risk factors are present.

Opinion piece: Coming soon, to a pharmacy near you.

Abstract  

Alemtuzumab induction in lung transplantation: time to move on?

This editorial puts into perspective the findings of the first randomized, controlled trial examining alemtuzumab induction for lung transplantation, and highlights the challenges encountered with alemtuzumab induction in other solid organs. See article by Jaksch et al on page 1839.

Coming Soon, to a Pharmacy Near You.

Abstract  

Bronchoalveolar lavage as a tool to predict, diagnose and understand bronchiolitis obliterans syndrome.

Bronchiolitis obliterans syndrome (BOS), a condition of irreversible small airway fibrosis, is the principal factor limiting long-term survival after lung transplantation. Bronchoscopy and bronchoalveolar lavage (BAL), techniques central to lung transplant clinical practice, provide a unique opportunity to interrogate the lung allograft during BOS development and identify potential disease mechanisms or biomarkers. Over the past 20 years, numerous studies have evaluated the BAL cellular composition, cytokine profiles and protein constituents in lung transplant recipients with BOS. To date, however, no summative evaluation of this literature has been reported. We developed and applied objective criteria to qualitatively rank the strength of associations between BAL parameters and BOS in order to provide a comprehensive and systematic assessment of the literature. Our analysis indicates that several BAL parameters, including neutrophil count, interleukin-8, alpha defensins and MMP-9, demonstrate highly replicable associations with BOS. Additionally, we suggest that considerable opportunity exists to increase the knowledge gained from BAL analyses in BOS through increased sample sizes, covariant adjustment and standardization of the BAL technique. Further efforts to leverage analysis of BAL constituents in BOS may offer great potential to provide additional in-depth and mechanistic insights into the pathogenesis of this complex disease.

Spirometrically significant acute rejection increases the risk for BOS and death after lung transplantation.

Acute rejection (AR) is a common complication following lung transplantation and is an established risk factor for bronchiolitis obliterans syndrome (BOS). AR clinical presentation varies considerably and is sometimes associated with an acute decrease in forced expiratory volume in 1 s (FEV1). We hypothesized that lung transplant recipients who experience such spirometrically significant AR (SSAR), as defined by a ≥10% decline in FEV1 relative to the prior pulmonary function test, are subsequently at increased risk for BOS and worse overall survival. In a large single center cohort (n = 339), SSAR occurred in 79 subjects (23%) and significantly increased the risk for BOS (p < 0.0001, HR = 3.2, 95% CI 2.3-4.6) and death (p = 0.0001, HR = 2.3, 95% CI 1.5-3.5). These effects persisted after multivariate adjustment for pre-BOS AR and lymphocytic bronchiolitis burden. An analysis of the subset of patients who experienced severe SSAR (≥20% decline in FEV1) resulted in even greater hazards for BOS and death. Thus, we demonstrate a novel physiological measure that allows discrimination of patients at increased risk for worse posttransplant outcomes. Further studies are needed to determine mechanisms of airflow impairment and whether aggressive clinical interventions could improve post-SSAR outcomes.

Portal hypertension and granulomatous liver disease in a lung transplant recipient due to disseminated atypical mycobacterial infection.

The incidence of atypical mycobacterial infection among solid organ transplant recipients is increasing. While lung transplant recipients in particular are at greater risk of atypical mycobacterial infection than other solid organ transplant recipients, it is typically confined to the lung and disseminated infection remains quite rare. We describe a case of disseminated Mycobacterium avium-complex (MAC) in a lung transplant recipient presenting as granulomatous liver disease with signs of portal hypertension. After identification of the infection and institution of proper therapy, the patient had significant improvement in both clinical signs of portal hypertension and liver function tests. Current literature suggests a favorable prognosis in most cases of MAC infection in lung transplant recipients with appropriate treatment. This case highlights the need to maintain an elevated index of suspicion for atypical pathogens with unusual clinical presentations among the lung transplant population.

A comparison of responses from olfactory receptor neurons of Heliothis subflexa and Heliothis virescens to components of their sex pheromone.

Single-cell electrophysiological recordings were obtained from olfactory receptor neurons in sensilla trichodea on male antennae of the heliothine species Heliothis subflexa and the closely related congener H. virescens. A large percentage of sensilla (72% and 81%, respectively, of all sensilla sampled) contained a single odor-responsive receptor neuron tuned to the major pheromone component of both species, Z-11-hexadecenal. A second population of sensilla on H. subflexa antennae (18%) housed receptor neurons that were tuned to Z-9-hexadecenal but also responded with less sensitivity to Z-9-tetradecenal. A similar population of sensilla (4%) on H. virescens male antennae housed receptor neurons that were shown to be tuned specifically only to Z-9-tetradecenal, with no response to even high dosages of Z-9-hexadecenal. A third population of sensilla (comprising 8% and 16% of the sensilla sampled in H. subflexa and H. virescens, respectively) housed two olfactory receptor neurons, one of which was tuned to Z-11-hexadecenyl acetate and the other tuned to Z-11-hexadecenol. In H. subflexa the Z-11-hexadecenyl acetate-tuned neuron also responded to Z-9-tetradecenal with nearly equivalent sensitivity. The behavioral requirements of males of these two species for distinct pheromonal blends was, therefore, reflected by the subtle differences in the tuning properties of antennal olfactory receptor neurons.

Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway.

The mammalian dual-specificity protein-tyrosine phosphatase VHR (for VH1-related) has been identified as a novel regulator of extracellular regulated kinases (ERKs). To identify potential cellular substrates of VHR, covalently immobilized mutant VHR protein was employed as an affinity trap. A tyrosine-phosphorylated protein(s) of approximately 42 kDa was specifically adsorbed by the affinity column and identified as ERK1 and ERK2. Subsequent kinetic analyses and transfection studies demonstrated that VHR specifically dephosphorylates and inactivates ERK1 and ERK2 in vitro and in vivo. Only the native structure of phosphorylated ERK was recognized by VHR and was inactivated with a second-order rate constant of 40,000 M-1 s-1. VHR was found to dephosphorylate endogenous ERK, but not p38 and JNK. Immunodepletion of endogenous VHR eliminated the dephosphorylation of cellular ERK. Transfection studies in COS-1 cells demonstrated that in vivo phosphorylation of epidermal growth factor-stimulated ERK depended on VHR protein levels. Overexpression above endogenous levels of VHR led to accelerated ERK inactivation, but did not alter the normal activation of ERK. Unique among reported mitogen activated protein kinase phosphatases, VHR is constitutively expressed, localized to the nucleus, and tyrosine-specific. This study is the first to report the identification of authentic substrates of dual-specificity phosphatases utilizing affinity absorbents and is the first to identify a nuclear, constitutively expressed, and tyrosine-specific ERK phosphatase. The data strongly suggest that VHR is responsible for the rapid inactivation of ERK following stimulation and for its repression in quiescent cells.

Behavioral antagonism in the moth Helicoverpa zea in response to pheromone blends of three sympatric heliothine moth species is explained by one type of antennal neuron.

We have discovered a type of sensillum on the antennae of male corn earworm moths, Helicoverpa zea, that houses two types of receptor neuron (RN) that explains both the upwind flight attraction of males to their own species' pheromone blend and arrestment to the quite similar blends emitted by females of three other sympatric North American heliothine species. The first RN type is a large-spiking neuron that is most sensitive to (Z)-9-hexadecenal (Z9-16:Ald), the secondary H. zea pheromone component that along with the major component, (Z)-11-hexadecenal, causes attraction to the female. This RN is also responsive to (Z)-9-tetradecenal (Z9-14:Ald; not a H. zea pheromone component) at higher dosages. The sensitivity of this RN thus explains the attraction that has been observed in other studies when small proportions of Z9-14:Ald are added to Z11-16:Ald to mimic the conspecific blend. The second type of RN in this sensillum is a small-spiking neuron that is again responsive to Z9-14:Ald (which in larger proportions acts as a strong antagonist to upwind flight), but this RN is actually more sensitive to two other strong behavioral antagonists, (Z)-11-hexadecenyl acetate and (Z)-11-hexadecenol. Thus, activation of this single broadly tuned 'antagonist' RN could explain why H. zea males will orient only to their conspecific females. These three compounds are emitted by females of three other North American species, H. subflexa, H. phloxiphaga, and H. virescens, as agonists in their blends, which also contain the H. zea components Z11-16:Ald and Z9-16:Ald. This antagonist RN may also explain why a blend of Z11-16:Ald and a small amount of Z9-14:Ald is never as attractive to H. zea males as the conspecific blend. Enhanced specificity for the conspecific blend arises because the antagonist RN is never stimulated to fire, even when large proportions of the pheromone component, Z9-16:Ald, are added to Z11-16:Ald. When Z9-14:Ald is used instead of Z9-16:Ald, however, and the proportion of Z9-14:Ald becomes too great, the threshold of the antagonist neuron as well as that of the agonist neuron is exceeded, and the upwind flight response begins to be suppressed.

Conotruncal cardiac anomalies and otitis media.

BACKGROUND: The neural crest influences the differentiation of the branchial arches, including the precursor tissue of the cardiac outflow tract and the eustachian tubes. Abnormal eustachian tubes are associated with otitis media. We hypothesized a relationship between conotruncal anomalies and eustachian tube anomalies. METHODS: We surveyed 115 nonsyndromic patients, aged 5 to 20 years, attending a state-run pediatric cardiology clinic. The cardiac anomalies were conotruncal (transposition of the great arteries, tetralogy of Fallot, or aortic stenosis) or nonconotruncal (atrial septal defect, tricuspid atresia, atrioventricular canal). Tympanic membrane photographs were categorized independently by two physicians as to normal, abnormal (scarred or other indication of otitis proneness), or indeterminate. RESULTS: For the 37 patients who had both ears categorized as normal or abnormal by both physicians, 20 of the 26 with a conotruncal anomaly had evidence of otitis media. In contrast, only 4 of 11 with nonconotruncal cardiac anomaly had evidence of otitis (p < 0.03; relative risk [conotruncal vs nonconotruncal], 5.83; 95% confidence interval, 1.26 to 26.95). CONCLUSION: The concept is supported that a neural crest determined branchial field defect influences the development of the cardiac outflow tract and the eustachian tubes. Children with congenital cardiac conotruncal anomalies are otitis media prone.

Quality and customers: Type 2 change in mental health delivery within health care reform.

The traditional separation of mental health and medical programs is problematic because mental health issues are inseparable from the larger medical system. By contrast, a collaborative primary care model of mental health care, augmented and supported by secondary specialty mental health services, has the potential to optimize quality and cost goals while reinforcing health care reform principles. The flexibility of mental health treatment in this delivery structure provides opportunities to customize services according to patient and purchaser expectations.

Electroantennographic and coupled gas chromatographic-electroantennographic responses of the mediterranean fruit fly,Ceratitis capitata, to male-produced volatiles and mango odor.

We have identified five compounds from the headspace of calling male Mediterranean fruit flies (medfly),Ceratitis capitata (Wiedemann), and three compounds from the headspace of ripe mango (Mangifera indica L). using coupled gas chromatographic-electroantennographic (GC-EAG) recordings, coupled gas chromatographic-mass spectrometric (GC-MS) analysis, and electroantennographic (EAG) assays of standards. The male-produced volatiles eliciting responses from female antennae were ethyl-(E)-3-octenoate, geranyl acetate, (E,E)-α-farnesene, linalool, and indole. An EAG dose-response test of linalool enantiomers and indole with female medfly antennae showed relatively strong EAG activities, but no significant difference between (R)-(-)-linalool and (S)-(+)-linalool. The three mango volatiles were identified as (1S)-(-)-ß-pinene, ethyl octanoate, andß-caryophyllene. In addition, a strong antennal response was recorded from a contaminant,α-copaene, present in a commercial sample ofß-caryophyllene. The EAG response amplitudes from both male and female antennae to the above three mango volatiles were significantly greater than to a hexanol control. For both male and female medfly antennae, the greatest EAG responses were elicited byß-caryophyllene followed by ethyl octanoate. The mean EAG responses of female antennae toß-caryophyllene and (1S)-(-)-ß-pinene were significantly greater than those of male antennae.

Quality and customers: a planning approach to the future of mental health services in a health maintenance organization.

Mental health service delivery is both a health care and business arrangement, and is accordingly impacted by national changes in both areas. HMO mental health services in the current health reform zeitgeist are being called on to provide more efficient, comprehensive integrated care. A planning effort is presented which is organized around (1) a quality improvement effort aimed at understanding who are the "customers" (patient, medical community, mental health staff, and client employer) and what they need and (2) coordination and integration with the HMO larger organizational plan and efforts. The unique benefits of staff model HMOs are discussed relative to mental health service.

Behavioral and electrophysiological activity of (Z,E)-7,9,11-dodecatrienyl formate, a mimic of the major sex pheromone component of carob moth,Ectomyelois ceratoniae.

The behavioral and electrophysiological activity of a mimic [(Z,E)7,9,11-dodecatrienyl formate] of the major sex pheromone component [(Z,E) 9,11,13-tetradecatrienal] of carob moth was assessed. Wind-tunnel bioassays demonstrated that the formate was as effective as natural gland extracts, and significantly more effective than the trienal alone or than the trienal blended with two minor pheromone components, in evoking source contact. Dispensers containing the formate were as effective as trienal-containing blend lures in attracting males when placed at the same dosage in traps in date gardens. Single-cell recordings showed that at least two olfactory neurons, differentiated by spike amplitude, are located in the long trichoid hairs on male carob moth antennae. Dose-response relationships indicated that puffs from cartridges loaded with at least 0.1 µg of the formate or of the trienal were necessary to elicit spiking by either the small or the large-spiking cell within a sensillum. Cross-adaptation studies demonstrated that both compounds stimulated the same large-spiking cell. The frequencies of spikes evoked from the large cell when stimulated by emissions from 0.1-µg, 1-µg, or 10-µg cartridges of either the formate or the trienal were not significantly different, suggesting that the formate is an effective mimic of the trienal at the antennal receptor cell level.

Identification and bioassay of sex pheromone components of carob moth,Ectomyelois ceratoniae (Zeller).

Three sex pheromone components of the carob moth were isolated and identified from the extract of female pheromone glands, using a variety of techniques including coupled gas chromatographic-electroantennographic recordings, coupled gas chromatographic-mass spectrometric analysis, microozonolysis, electroantennographic assays of monounsaturated standards, wind-tunnel bioassays, and field trials. The major component was identified as (Z,E)-9,11,13-tetradecatrienal, a novel lepidopterous pheromone component structure. Two minor components, either one of which improves the upwind flight response of males when blended with the major component, were identified as (Z,E)-9,11-tetradecadienal, and (Z)-9-tetra-decenal.

Interaction between visual and olfactory stimuli during host-finding by leafhopper,Dalbulus maidis (Homoptera: Cicadellidae).

Virtually nothing is known about the role plant volatiles play in host-finding by Homoptera in the Suborder Auchenorrhyncha. In laboratory bioassays, we examined the influence of plant volatiles on orientation and postcontact behaviors of the leafhopper,Dalbulus maidis, and determined the relationship between visual and olfactory stimuli during host-finding. When compared to the number of contacts made with reflected green light in the presence of a hexane control,D. maidis made more contacts when exposed to volatile extracts from its preferred host, maize; a similar number of contacts when exposed to volatiles from a marginal host, gamagrass; and fewer contacts when exposed to volatiles from a nonhost, sorghum. There was no difference between males and females in the number of contacts made with green light when exposed to maize volatiles compared to hexane alone. More contacts were made with green light than with white light of similar intensity, both in the presence and in the absence of olfactory stimuli; however, maize volatiles acted as a Synergist by increasing the number of contacts leafhoppers made with green light. After contacting the green light, exposure of maize volatiles significantly increased, relative to hexane, the amount of stationary time, but did not influence the amount of time spent moving, the distance traveled, or the speed while moving when within the boundaries of the green light. This study provides the first evidence for an interaction between visual and olfactory stimuli during host-finding for a leafhopper and also for olfactory mediation of postcontact behaviors not associated with feeding.

Congenital cardiac outflow tract anomalies and otitis media.

The neural crest is involved in the differentiation of the cardiac outflow tract and branchial arches. Branchial arches one and two give rise to the eustachian tubes. Anatomically different eustachian tubes (e.g., short length) are found in persons prone to otitis media. We hypothesized a relationship between outflow tract anomalies and eustachian tube anomalies. The medical records of 238 children with a catheterization diagnosis of congenital heart disease were reviewed for otitis diagnoses. Children with syndromes known to be associated with recurring otitis media were excluded. Recurrent otitis media was recorded in 32.2% of those with outflow tract anomaly, significantly (P less than 0.03) higher than the 18.9% rate in children with a cardiac anomaly not involving the outflow tract. Neither race, sex, nor cyanosis seemed to account for the differing rates of otitis. These data may support the concept of a field defect arising from neural crest cells that influences the development of the cardiac outflow tract and eustachian tubes.