Yuna C. Larrabee

Acid aspiration-induced airways hyperresponsiveness in mice

The role of gastroesophageal reflux and micro-aspiration as a trigger of airways hyperresponsiveness (AHR) in patients with asthma is controversial. The role of acid reflux and aspiration as a direct cause of AHR in normal subjects is also unclear. We speculated that aspiration of a weak acid with a pH (1.8) equivalent to the upper range of typical gastric contents would lead to AHR in naive mice. We further speculated that modest reductions in aspirate acidity to a level expected during gastric acid suppression therapy (pH 4.0) would impede aspiration-induced AHR. BALB/c female mice were briefly anesthetized with isoflurane and allowed to aspirate 75 microl of saline with HCl (pH 1.8, 4.0, or 7.4) or underwent sham aspiration. Mice were re-anesthetized 2 or 24 h later, underwent tracheostomy, and were coupled to a mechanical ventilator. Forced oscillations were used to periodically measure respiratory impedance (Zrs) following aerosol delivery of saline and increasing doses of methacholine to measure for AHR. Values for elastance (H), airways resistance (R(N)), and tissue damping (G) were derived from Zrs. Aspirate pH of 1.8 led to a significant overall increase in peak R(N), G, and H compared with pH 4.0 and 7.4 at 2 and 24 h. Differences between pH 7.4 and 4.0 were not significant. In mice aspirating pH 1.8 compared with controls, airway lavage fluid contained more neutrophils, higher protein, and demonstrated higher permeability. We conclude that acid aspiration triggers an acute AHR, driven principally by breakdown of epithelial barrier integrity within the airways.

Activation of the Hetero-octameric ATP Phosphoribosyl Transferase through Subunit Interface Rearrangement by a tRNA Synthetase Paralog

ATP phosphoribosyl transferase (ATP-PRT) joins ATP and 5-phosphoribosyl-1-pyrophosphate (PRPP) in a highly regulated reaction that initiates histidine biosynthesis. The unusual hetero-octameric version of ATP-PRT includes four HisGS catalytic subunits based on the periplasmic binding protein fold and four HisZ regulatory subunits that resemble histidyl-tRNA synthetases. Here, we present the first structure of a PRPP-bound ATP-PRT at 2.9 Å and provide a structural model for allosteric activation based on comparisons with other inhibited and activated ATP-PRTs from both the hetero-octameric and hexameric families. The activated state of the octameric enzyme is characterized by an interstitial phosphate ion in the HisZ-HisG interface and new contacts between the HisZ motif 2 loop and the HisGS dimer interface. These contacts restructure the interface to recruit conserved residues to the active site, where they activate pyrophosphate to promote catalysis. Additionally, mutational analysis identifies the histidine binding sites within a region highly conserved between HisZ and the functional HisRS. Through the oligomerization and functional re-assignment of protein domains associated with aminoacylation and phosphate binding, the HisZ-HisG octameric ATP-PRT acquired the ability to initiate the synthesis of a key metabolic intermediate in an allosterically regulated fashion.

Neither Fibrin nor Plasminogen Activator Inhibitor-1 Deficiency Protects Lung Function in a Mouse Model of Acute Lung Injury

Fibrin impairs surfactant function in vitro, and inhibition of fibrinolysis by plasminogen activator inhibitor (PAI-1) is thought to promote fibrin accumulation in acute lung injury (ALI). This has led to speculation that impaired PAI-1 and fibrin accumulation should protect lung function in ALI. We tested this hypothesis by investigating ALI severity in fibrinogen-deficient (Fgn-/-) and PAI-1-deficient (PAI-1-/-) mice. PAI-1-/-, C57BL/6, Fgn-/-, and Fgn+/- females were anesthetized and allowed to aspirate 4 microl/g of hydrochloric acid (pH 1.0) and then reanesthetized and connected to a ventilator 48 h later. Naive C57BL/6 and Fgn+/- females served as controls. Following deep inflation (DI), forced oscillations were delivered periodically over 8 min to measure changes in elastance (H) as a surrogate of lung derecruitment, at positive end-expiratory pressures (PEEP) of 6, 3, and 1 cmH(2)O. Increases in H following DI in acid-injured mice were greater than naive strain-matched controls. Increases in H were no different between injured PAI-1-/- and C57BL/6, or between injured Fgn-/- and +/- mice, at any PEEP. Pressure-volume curves were no different between injured groups. Total lung fibrin was lower in injured PAI-1-/- and Fgn-/- mice relative to injured C57BL/6 and Fgn+/- mice, respectively, but indices of permeability were no different between strains. Unexpectedly, neither fibrin nor PAI-1 deficiency protects lung mechanical function in mice with acid-induced ALI. We speculate that in vivo lung function may be more closely tied to permeability and alveolar protein in general, rather than being linked specifically to fibrin.

Association of common variants, not rare mutations, in IRF6 With nonsyndromic clefts in a honduran population†

Cleft lip with or without cleft palate (CL/P) is a common birth defect throughout the world. Linkage studies have shown interferon regulatory factor 6 (IRF6) to be associated with CL/P in multiple populations, including one in Honduras. It is unknown, however, whether rare sporadic mutations or common variants are the cause of this association, and reports exist supporting both hypotheses. Thus, it is important to determine the cause for this association in a Honduran population.

Which inferior turbinate reduction technique best decreases nasal obstruction

BACKGROUND Chronic nasal obstruction can significantly impair patients’ quality of life and is a frequent complaint seen by otolaryngologists. Inferior turbinate hypertrophy is a common cause of chronic nasal obstruction. Various etiologies for the hypertrophy of inferior turbinates include allergic reactions, nonallergic rhinitis, chronic hypertrophic rhinitis, and compensatory hypertrophy as seen in septal deviation. Conservative medical treatment options include topical decongestants and corticosteroids, antihistamines, systemic decongestants, mast cell stabilizers, and immunotherapy. However, in patients who have failed medical management, surgical reduction of the inferior turbinates is an effective treatment. Many surgical techniques exist to reduce the size of the inferior turbinates. Conventional surgical options include partial or total turbinectomy, turbinoplasty, electrocautery, cryotherapy, laser cautery, submucosal resection, and submucosal resection with lateral displacement. Newer techniques include radiofrequency-assisted turbinoplasty, microdebrider-assisted turbinoplasty, and ultrasound turbinate reduction. There is no consensus as to which surgical technique is most effective in decreasing nasal obstruction.

Novel IRF6 mutations in Honduran Van der Woude syndrome patients.

Van der Woude syndrome (VWS) is an autosomal dominant inherited disease characterized by lower lip pits, cleft lip and/or cleft palate. Missense, nonsense and frameshift mutations in IRF6 have been revealed to be responsible for VWS in European, Asian, North American and Brazilian populations. However, the mutations responsible for VWS have not been studied in Central American populations. Here, we investigated the role of IRF6 in patients with VWS in a previously unstudied Honduran population. IRF6 mutations were identified in four out of five VWS families examined, which strongly suggests that mutations in IRF6 are responsible for VWS in this population. We reported three novel mutations and one previously described mutation. In the first family, a mother and daughter both exhibited a p.N88I mutation in the DNA-binding region of IRF6 that was not present in unaffected family members. In the second, we found a unique p.K101QfsX15 mutation in the affected patient, leading to a frameshift and early stop codon. In the third, we identified a p.Q208X mutation occurring in exon 6. In the fourth, we found a nonsense mutation in exon 9 (p.R412X), previously described in Brazilian and Northern European populations. In the fifth, we did not identify any unique exonic missense, nonsense or frameshift mutations. This study reports the first cases of IRF6 mutations in VWS patients in a Central American population, further confirming that the causal link between IRF6 and VWS is consistent across multiple populations.

Use of continuous positive airway pressure after rhinoplasty, septoplasty, and sinus surgery: A survey of current practice patterns.

To explore current practice patterns in the use of continuous positive airway pressure (CPAP) following nasal or sinus surgery.

Intradermal testing after negative skin prick testing for patients with high suspicion of allergy

Skin testing is a widely accepted method for identifying inhalant allergies. Intradermal (ID) testing is often performed after negative skin prick testing (SPT) when a practitioner has a high level of clinical suspicion for a particular allergen.Background Skin testing is a widely accepted method for identifying inhalant allergies. Intradermal (ID) testing is often performed after negative skin prick testing (SPT) when a practitioner has a high level of clinical suspicion for a particular allergen. Methods A retrospective chart review study was performed over a 5-year period in patients with negative SPT for airborne allergens who also underwent ID testing based on a high level of suspicion for clinical allergy. Results Eighty-seven patients had negative SPT and went on to receive an average of 7 ID tests per patient. A total of 592 ID tests were performed after negative SPT. Of these, 20.8% (123/592) had a positive ID result with negative SPT. The allergens with the greatest percentage of positive ID results with negative SPTs were dog, cat, D. farinae, and D. pteronyssinus (33.3%, 34.3%, 39.4%, and 39.6%, respectively). The allergens least likely to test positive on ID testing after negative SPT were red maple, Cladosporium, and Alternaria (0%, 6.3%, and 6.5%, respectively). Conclusion Approximately 20% of all negative results on SPT will have a positive ID test, more likely for indoor allergens. If a high suspicion for allergy exists in a patient with a negative SPT result, it may be useful to proceed with ID testing. However, the clinical significance of a positive ID test after negative SPT still needs to be elucidated.

Trends in Nasal Subunit Reconstruction by Facial Plastic and Reconstructive Surgeons

Abstract To determine if facial plastic and reconstructive surgeons still adhere to the classic nasal subunit principle as described by Burget and Menick. Observational survey. A Weill Cornell Medicine institutional review board approved electronic survey that was sent via e‐mail to active members of the American Academy of Facial Plastic and Reconstructive Surgery (AAFPRS). The survey consisted of 32 multiple‐choice questions pertaining to the operative management of small (22‐30%), medium (50‐58%), and large (75‐81%) defects of each subunit of the nose, as well as demographic, provider, and practice characteristics. There were 111 responses to the survey (10.1% response rate). Ninety‐eight percent of respondents reported familiarity with the subunit principle, and 59.6% considered the subunit principle in greater than 90% of cases. Almost three‐quarters (70.4%) of respondents felt the subunit principle should be applied but could be modified based on the particular nasal defect, whereas 28.7% felt it was only sometimes helpful and was not mandatory for successful nasal reconstruction. Large defects of the tip and ala are generally treated by excision of the remaining subunit (79.4 and 80.6%, respectively). Fewer surgeons would excise the remaining subunit for large defects of the dorsum (39.8%), sidewall (38.8%), and soft tissue facet (18.4%). Simple repair without additional excision was the treatment of choice for small defects of the tip (58.2%), ala (59.2%), sidewall (65%), dorsum (68%), and soft tissue facet (71.8%). However, in many small‐ (up to 32%) and medium‐ (up to 51%) sized defects of the tip, ala, sidewall, and dorsum, respondents reported partial subunit excision. The majority of AAFPRS members abide to the classical subunit principle by completely excising the remaining subunit for large defects of the tip and ala. Many surgeons modify the subunit principle in small and medium defects.

Reconstruction of Mohs Defects of the Lips and Chin

Reconstruction of defects of the lips after Mohs micrographic surgery should encompass functional and aesthetic concerns. The lower lip and chin compose two-thirds of the lower portion of the face. The focus of this article is local tissue transfer for primarily cutaneous defects after Mohs surgery. Various flaps exist for repair. For small defects, elliptical excision with primary closure is a viable option. During reconstruction of the lip, all of the involved layers need to be addressed, including mucosa, muscle, and the vermillion or cutaneous lip. It is especially important to realign the vermillion border precisely for optimal results.