New insights into mechanism of Eustachian tube ventilation based on cine computed tomography images

There is debate concerning the mechanism of Eustachian tube (ET) ventilation. While a mechanism of complete opening has been advocated previously, sequential contraction of the levator veli palatini and medial pterygoid muscles followed by the tensor veli palatini and lateral pterygoid muscles may produce a transient sequential opening mechanism, allowing an air bolus to traverse the ET. This may explain confusion surrounding sonotubometry reports that not every swallow leads to sound passage in normal subjects. We hypothesize that the ET may not need to open completely when ventilating the middle ear; rather, a discrete air bolus can pass through it. Five normal and five disordered subjects underwent low-radiation dose cine computed tomography (CT) scans of the ET. Sixteen contiguous 2.5?mm slice locations were chosen through a 4?cm area in the nasopharynx that were parallel to and encompassed the entire ET. Twelve images were acquired at each slice over 4.8?s during swallowing and other tasks. Serial images were analyzed. An air bolus was observed passing through the ET in the normal subjects, but not the subject with ET dysfunction. Medial and lateral pterygoid contractions were also observed. A new hypothetical mechanism of transient sequential ET ventilation is presented. This is not a definitive conclusion, as the number of scans taken and maneuvers used was limited. Improved understanding of ET ventilation may facilitate management of middle ear disease as treatment evolves from ventilatory tube placement to ET manipulation.     

Insights into the Progression of Labile Hb A1c to Stable Hb A1c via a Mechanistic Assessment of 2,3-Bisphosphoglycerate Facilitation of the Slow Nonenzymatic Glycation Process

Nonenzymatic glycation (NEG) of human hemoglobin (Hb A) consists of initial non covalent, reversible steps involving glucose and amino acid residues, which may also involve effector reagent(s) in the formation of labile Hb A_1c (the conjugate acid of the Schiff base). Labile Hb A_1c can then undergo slow, largely irreversible, formation of stable Hb A_1c (the Amadori product). Stable Hb A_1c is measured to assess diabetic progression after labile Hb A_1c removal. This study aimed to increase the understanding of the distinctions between labile and stable Hb A_1c from a mechanistic perspective in the presence of 2,3-bisphosphoglycerate (2,3-BPG). 2,3-Bisphosphoglycerate is an effector reagent that reversibly binds in the Hb A_1c pocket and modestly enhances overall NEG rate. The deprotonation of C2 on labile Hb A_1c in the formation of the Amadori product was previously proposed to be rate-limiting. Computational chemistry was used here to identify the mechanism(s) by which 2,3-BPG facilitates the deprotonation of C2 on labile Hb A_1c. 2,3-Bisphosphoglycerate is capable of abstracting protons on C2 and the α-nitrogen of labile Hb A_1c and can also deprotonate water and/or amino acid residues, therefore preparing these secondary reagents to deprotonate labile Hb A_1c. Parallel reactions not leading to an Amadori product were found that include formation of the neutral Schiff base, dissociation of glucose from the protein, and cyclic glycosylamine formation. These heretofore under appreciated parallel reactions may help explain both the selective removal of labile from stable Hb A_1c and the slow rate of NEG.     

Acute exacerbation of chronic obstructive pulmonary disease: Influence of social factors in determining length of hospital stay and readmission rates

BACKGROUND:

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is the leading reason for hospitalization in Canada and a significant financial burden on hospital resources. Identifying factors that influence the time a patient spends in the hospital and readmission rates will allow for better use of scarce hospital resources.

OBJECTIVES:

To determine the factors that influence length of stay (LOS) in the hospital and readmission for patients with AECOPD in an inner-city hospital.

METHODS:

Using the Providence Health Records, a retrospective review of patients admitted to St Paul’s Hospital (Vancouver, British Columbia) during the winter of 2006 to 2007 (six months) with a diagnosis of AECOPD, was conducted. Exacerbations were classified according to Anthonisen criteria to determine the severity of exacerbation on admission. Severity of COPD was scored using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. For comparative analysis, severity of disease (GOLD criteria), age, sex and smoking history were matched.

RESULTS:

Of 109 admissions reviewed, 66 were single admissions (61%) and 43 were readmissions (39%). The number of readmissions ranged from two to nine (mean of 3.3 readmissions). More than 85% of admissions had the severity of COPD equal to or greater than GOLD stage 3. The significant indicators for readmission were GOLD status (P<0.001), number of related comorbidities (OR 1.47, 95% CI 1.10 to 1.97; P<0.009) and marital status (single) (OR 4.18, 95% CI 1.03 to 17.02; P<0.046). The requirement for social work involvement during hospital admission was associated with a prolonged LOS (P<0.05).

CONCLUSIONS:

The results of the present study show that disease severity (GOLD status) and number of comorbidities are associated with readmission rates of patients with AECOPD. Interestingly, social factors such as marital status and the need for social work intervention are also linked to readmission rates and LOS, respectively, in patients with AECOPD.     

Consequences of multiple withdrawals from alcohol

This article represents the proceedings of a symposium at the 2003 annual meeting of the Research Society on Alcoholism in Fort Lauderdale, FL, organized by Theodora Duka and chaired by Dai Stephens. The purpose of the symposium was to examine the effects of multiple experiences of withdrawal from alcohol in animals made dependent on alcohol and in humans who are alcohol dependent. Parallels were drawn to the effects of repeated short-lived high-content alcohol exposures in animals and in humans who are social drinkers but indulge in binge drinking. The presentations were (1) Multiple detoxifications and risk of relapse in abstinent alcoholics, by John Gentry and Robert Malcolm; (2) Emotional and cognitive impairments after long-term use of alcohol: relationship to multiple detoxifications and binge drinking, by Theodora Duka; (3) The effect of repeated withdrawal from ethanol on conditioning to appetitive stimuli, by Tamzin Ripley, Gilyanna Borlikova, and Dai Stephens; (4) Alcohol withdrawal kindling: electrographic measures in a murine model of behavioral seizure sensitization, by Lynn Veatch and Howard Becker; and (5) Binge drinking induced changes in CNS, by Fulton Crews.     

Further delineation of the KBG syndrome caused by ANKRD11 aberrations

Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.     

Human Factor IX in Animals: Kinetics from Isolated, Radiolabelled Protein and Platelet Destruction following Crude Concentrate Infusions

S ummary Crude, concentrated and isolated, labelled human factor IX was prepared and infused into animals. Initially, two dogs with severe haemophilia B received both preparations and factor IX clotting activity and label survived well. Kinetic parameters fit a two-compartment open model.
For 12 infusions of concentrates into normal baboons, clotting and antigen data again fit the model. Similar kinetics, with less variability, were found for nine infusions of [¹²⁵I]factor IX. Radioactivity of the first post-infusion samples was >90% precipitated in the double antibody system with an average of 84% of counts adsorbable to barium citrate. Compared to plasma, barium adsorbable counts gave a shorter t _1/2β-elimination phase suggesting a small recirculating ¹²⁵iodide pool. When [¹²⁵I]factor IX was rechromatographed over heparin-agarose, variable amounts of altered, labelled protein were present; this species was more rapidly cleared from plasma post-infusion.
Twelve infusions of crude concentrates into baboons were given to animals whose platelets had been labelled with ⁵¹Cr. Platelet counts as well as survival were then followed. For seven of these animals, mean counts decreased and the labelled platelets were destroyed, to an average of 21%, during the first 4 h post-infusion. Subsequent platelet survival was normal. Three infusions of gel-filtered, crude concentrates and two infusions of 'activated'commercial concentrates did not significantly alter platelet survival.     

Clinical features and outcome of T-cell acute lymphoblastic leukemia in childhood with respect to alterations at the TAL1 locus: a Pediatric Oncology Group study

Alteration of the TAL1 locus is the most common nonrandom genetic defect in childhood T-cell acute lymphoblastic leukemia (T-ALL). To determine if rearrangements of the TAL1 proto-oncogene confer a distinct leukemic phenotype, we studied leukemic peripheral blood or bone marrow samples from 182 children with newly diagnosed T-ALL enrolled on Pediatric Oncology Group treatment protocols. Forty-eight (26%) of the samples had a local rearrangement of the TAL1 locus. Demographic and clinical features were compared for patient subgroups with and without TAL1 rearrangements. The only clinical correlates that were significantly associated with TAL1 gene rearrangements were higher white blood cell count (P = .017) and higher hemoglobin (P = .007) at diagnosis. Immunophenotypically, samples with altered TAL1 were more likely to be CD2+ (P = .001) and lack CD10 (cALLa) expression (P = .007) than those without the rearrangement. There was a trend toward improved event-free survival (EFS) in patients with TAL1 rearrangements (4-year EFS was 44% +/- 7% for patients without the rearrangements v 59% +/- 11% for those with rearrangements), but the difference was not significant (P = .34). The role of TAL1 in leukemogenesis has yet to be clearly defined, and the prognostic significance of TAL1 gene rearrangements in T-ALL deserves further study.     

IgMs produced by two acquired immune deficiency syndrome lymphoma cell lines: Ig binding specificity and VH-gene putative somatic mutation analysis [published erratum appears in Blood 1994 Aug 1;84(3):995]

Two B-cell lines, 2F7 and 10C9, were established by single cell cloning from biopsies obtained from two acquired immune deficiency syndrome patients with Burkitt's lymphoma. Representation of the original tumors was verified by demonstration of (1) identical biallelic rearrangement of Ig genes for 2F7 and (2) shared idiotype for 10C9. Both cell lines displayed cell-surface Ig and secreted Ig (IgM lambda for 2F7, IgM kappa for 10C9). IgMs from both cell lines immunoprecipitated actin; in addition, 2F7 IgM lambda immunoprecipitated recombinant human immunodeficiency virus type 1 (HIV-1) gp 160. 2F7 IgM lambda did not react with other autoantigens (double-stranded and single-stranded DNA, actin, bovine serum albumin, IgG), whereas 10C9 IgM kappa reacted with human IgG. The 2F7 IgM heavy-chain variable region (VH) showed a 95% nucleotide homology with a previously sequenced VHIII germline gene, hv3019b9, whereas the 10C9 IgM VH showed a 95% homology with a previously sequenced VHIV germline gene, VH4.21. Use of minimally modified VH genes and demonstration of reactivity with chronically present antigens (ie, actin, HIV-1 gp 160, or human IgG) suggests that B cells in HIV-1-infected individuals proliferating in response to chronic antigenic stimulation may be at increased risk for lymphomagenesis.