Variability of Swallow-associated Sounds in Adults and Infants

We previously used cervical auscultation (CA) to describe the stability of swallow-associated sounds of infant feeding. To date, no similar studies have been performed in adults. The objectives of this study were to identify the initial discrete sounds (IDS) of adult swallows and compare the stability of IDS signals in infants to that of adults. We performed CA with a microphone and accelerometer fixed simultaneously to the neck of 20 healthy adults. Each participant consumed a liquid, puree, and solid. The microphone and accelerometer collected signals of similar duration. The variance index (VI), an assessment of the stability of the IDS, was compared in adults and a group of low-risk preterm infants. The VI of adults swallowing liquid (29.1 [24.1, 36.6] {25%, 75%}) did not differ from that of preterm infants older than 36 weeks PMA (36.3 [33.4, 41.9]), but was lower than the VI of infants younger than 36 weeks PMA (49.0 [46.4, 51.1]; p < 0.05). This is the first real-time comparison of microphones and accelerometers for CA. The stability of IDS of low-risk preterm infants approaches that of normal adults as the infants age. Because successful feeding in infants is often used as a surrogate for normal development, the stability of swallow-associated sounds deserves more investigation as a potential marker for neurologic well-being.

Extracellular superoxide dismutase regulates cardiac function and fibrosis

Extracellular superoxide dismutase (EC-SOD) is an antioxidant that protects the heart from ischemia and the lung from inflammation and fibrosis. The role of cardiac EC-SOD under normal conditions and injury remains unclear. Cardiac toxicity, a common side effect of doxorubicin, involves oxidative stress. We hypothesize that EC-SOD is critical for normal cardiac function and protects the heart from oxidant-induced fibrosis and loss of function. C57BL/6 and EC-SOD-null mice were treated with doxorubicin, 15 mg/kg (i.p.). After 15 days, echocardiography was used to assess cardiac function. Left ventricle (LV) tissue was used to assess fibrosis and inflammation by staining, Western blot, and hydroxyproline analysis. At baseline, EC-SOD-null mice have LV wall thinning and increases in LV end diastolic dimensions compared to wild-type mice but have normal cardiac function. After doxorubicin, EC-SOD-null mice have decreases in fractional shortening not apparent in WT mice. Lack of EC-SOD also leads to increases in myocardial apoptosis and significantly more LV fibrosis and inflammatory cell infiltration. Administration of the metalloporphyrin AEOL 10150 abrogates the loss of cardiac function, and potentially fibrosis, associated with doxorubicin treatment in both wild-type and EC-SOD KO mice. EC-SOD is critical for normal cardiac morphology and protects the heart from oxidant-induced fibrosis, apoptosis, and loss of function. The antioxidant metalloporphyrin AEOL 10150 effectively protects cardiac function from doxorubicin-induced oxidative stress in vivo. These findings identify targets for the use of antioxidant agents in oxidant-induced cardiac fibrosis.     

Transforming growth factor beta (TGF-beta), a potent inhibitor of erythropoiesis: neutralizing TGF-beta antibodies show erythropoietin as a potent stimulator of murine burst-forming unit erythroid colony formation in the absence of a burst-promoting activity

Transforming growth factor beta (TGF-beta) is a bifunctional regulator of the growth of myeloid progenitors and is here demonstrated to directly inhibit the growth of primitive erythroid progenitors by 95% to 100% regardless of the cytokines stimulating growth. Autocrine TGF- beta production of primitive hematopoietic progenitors has previously been reported. In the present study, a neutralizing TGF-beta antibody (anti-TGF-beta) added to serum-containing cultures, resulted in a 3-, 4- , and 25-fold increase in burst-forming unit erythroid (BFU-E) colony formation in response to interleukin-4 (IL-4) plus erythropoietin (Epo), SCF plus Epo, and IL-11 plus Epo, respectively. The growth of BFU-E progenitors has been suggested to require a burst-promoting activity in addition to Epo. Accordingly, we observed no BFU-E colony formation in serum-containing cultures in response to Epo alone. In contrast, 50 BFU-E colonies were formed when anti-TGF-beta was included in the culture. In serum-free cultures, Epo also stimulated BFU-E colony formation in the absence of other cytokines, whereas anti-TGF- beta had no effect on the number of colonies formed. Quantitation of TGF-beta 1 in serum by an enzyme-linked immunosorbent assay method showed predominantly the presence of precursor (latent) TGF-beta 1, but also showed active TGF-beta 1 at a concentration sufficient to potently inhibit erythroid colony formation. Thus, neutralization of active TGF- beta 1 in serum shows that Epo alone is sufficient to stimulate the growth of murine BFU-E progenitors.     

Immunophenotypic analysis of reticulocytes in paroxysmal nocturnal hemoglobinuria

The hematologic disorder paroxysmal nocturnal hemoglobinuria (PNH) occurs following an acquired somatic mutation in the Piga gene within a bone marrow stem cell. The progeny of this mutated cell cannot synthesize glycosylphosphatidylinositol (GPI) anchors, with a resultant deficiency in surface expression of all GPI-linked proteins. The protean clinical manifestations of PNH presumably result from the deficiency of these GPI-linked surface proteins. To explain the observation that neutrophils are affected at a significantly higher percentage than circulating erythrocytes and to analyze the proliferative rates of erythroid production in PNH, we studied 25 patients using flow cytometry. The fluorescent dye thiazole orange was used to detect reticulocytes, and CD59 monoclonal antibody was used to identify GPI-deficient cells. In contrast to the mature circulating erythrocytes, the percentage of abnormal reticulocytes was similar to the percentage of affected neutrophils. However, the vast majority of reticulocytes was completely GPI-deficient, ie, were type III cells, even in patients with only modest numbers of circulating type III erythrocytes. In addition, greater than 5% type II reticulocytes were identified in only 3 patients, although greater than 5% type II mature erythrocytes were identified in 10 of 25 patients. The results show that the erythroid and neutrophil bone marrow precursors have an equivalent proliferative advantage in PNH. The data also have important implications for the origin of type-II erythrocytes in PNH.     

Mandibular advancement splint titration in obstructive sleep apnoea

Introduction  Mandibular advancement splints (MAS) allowing self-adjustment may be better tolerated, but the optimum titration protocol needs systematic study. Aim  The aims of the study are to assess the effectiveness of a titratable MAS device in consecutive patients with body mass index (BMI) < 35 kg/m² and obstructive sleep apnoea [OSA, apnoea–hypopnoea index (AHI) 10–40/h] and compare two methods of adjustment [self-adjustment or adjustment after polysomnographic (PSG) feedback]. Materials and methods  Twenty-eight patients (24 M, mean age 49 years, mean BMI 27.6 kg/m²) with symptomatic (Epworth Sleepiness score > 8/24, snoring, choking or poor sleep quality) OSA (mean AHI 25.7/h, range 10–46/h) had a MAS set at 70% maximal protrusion and were randomised to subjective self-adjustment for 6 weeks (n = 16) or objective adjustment (n = 12; fixed position for 3 weeks, then PSG based feedback at 3 weeks with self-adjustment instructions). Primary outcome variable (AHI) and OSA symptoms were compared by t tests and chi-squared tests at baseline and after 6 weeks. Resolution of apnoea was defined as AHI < 5/h; improvement was defined as AHI decreased by >50% but still >5/h. Results  The groups had similar baseline demographics, OSA severity and occlusal type. MAS therapy improved or resolved OSA in 20 out of 28 (71%) and was reportedly used nightly by 91% of the objective group and 63% of the subjective group (p = 0.04). MAS were used all night by 75% of the objective group and 69% of the subjective group (p > 0.05). MAS adjustment following PSG feedback did not lower AHI further from 3 weeks (baseline 26.5 ± 12.0/h, 3 weeks 15.3 ± 13.5/h p = 0.01, 6 weeks 11.7 ± 10.0/h, p = 0.11). The overall improvement was similar to that achieved with subjective adjustment (baseline AHI 25.4 ± 7.4/h, 6 weeks 14.3 ± 10.7/h, p = 0.0002). Symptomatic benefit was reported by both groups. Conclusion  In selected patients, titratable MAS improved or resolved OSA in the majority of patients and was well tolerated. PSG-based feedback at 3 weeks allowed objective confirmation of efficacy and increased device use but did not result in greater improvement in AHI or symptoms. Neither titration method was significantly superior for us to provide firm endorsement. However, we recommend a follow-up sleep study to confirm MAS efficacy.     

Inducibility of Atrial Fibrillation with a Synchronized External Low Energy Shock Post-Pulmonary Vein Isolation Predicts Recurrent Atrial Fibrillation

Background: Inducibility of atrial fibrillation (AF) with burst pacing after pulmonary vein (PV) isolation is associated with recurrent AF.
Objective: This study evaluated whether an external 30 Joule (J) shock synchronized to the R wave, during the vulnerable period of atrial repolarization, is able to risk-stratify patients further for AF recurrence after PV isolation.
Methods: One hundred and sixteen consecutive patients underwent PV isolation for AF. Atrial burst pacing was performed after PV isolation. In patients without AF induced by burst pacing, a biphasic external 30 J shock synchronized to the R wave was delivered as a further test for inducible AF. Patients were followed for a mean of 16 months, and recurrent AF was defined as more than 10 sec of AF on ambulatory monitoring.
Results: AF was induced in 19 (16%) of patients with burst pacing. Eighty-one patients who were noninducible with burst pacing had a 30 J shock administered, which induced AF in 16 (20%). In follow-up, 21% of patients who were noninducible with burst pacing or low-energy shock vs 54% who were inducible with either test developed recurrent AF at one year (HR 3.18, P = 0.0004 on multivariate analysis). Among patients who were noninducible with burst pacing, 18% who were noninducible with a low-energy shock vs 60% who were inducible with shock developed recurrent AF at one year (HR = 4.63, P = 0.0006 on multivariate analysis).
Conclusion: Inducibility of AF by a 30 J shock delivered during atrial repolarization after PV isolation may predict AF recurrence. Evaluation of inducibility of AF with burst pacing and a biphasic external synchronized shock after PV isolation may help guide postprocedure management.     

A positive 2-item Patient Health Questionnaire depression screen among hospitalized heart failure patients is associated with elevated 12-month mortality

BackgroundGiven the association of depression with poorer cardiac outcomes, an American Heart Association Science Advisory has advocated routine screening of cardiac patients for depression using the 2-item Patient Health Questionnaire (PHQ-2) “at a minimum.” However, the prognostic value of the PHQ-2 among HF patients is unknown.Methods and ResultsWe screened hospitalized HF patients (ejection fraction [EF] <40%) that staff suspected may be depressed with the PHQ-2, and then determined vital status at up to 12-months follow-up. At baseline, PHQ-2 depression screen–positive patients (PHQ-2+; n = 371), compared with PHQ-2 screen–negative patients (PHQ-2?; n = 100), were younger (65 vs 70 years) and more likely to report New York Heart Association (NYHA) functional class III/IV than class II symptoms (67% vs. 39%) and lower levels of physical and mental health–related quality of life (all P ≤ .002); they were similar in other characteristics (65% male, 26% mean EF). At 12 months, 20% of PHQ-2+ versus 8% of PHQ-2? patients had died (P = .007) and PHQ-2 status remained associated with both all-cause (hazard ratio [HR] 3.1, 95% confidence interval [CI] 1.4–6.7; P = .003) and cardiovascular (HR 2.7, 95% CI 1.1–6.6; P = .03) mortality even after adjustment for age, gender, EF, NYHA functional class, and a variety of other covariates.ConclusionsAmong hospitalized HF patients, a positive PHQ-2 depression screen is associated with an elevated 12-month mortality risk.     

Toll-like receptor 4 signaling in T cells promotes autoimmune inflammation

Toll-like receptors (TLRs) are critical components of innate immunity and function as rapid pathogen sensors. TLR4 is expressed on CD4(+) T cells as well, the functional significance of which is unclear. In this study, we analyzed the function of TLR4 in T cells but did not find a role in promoting T helper (Th) cell polarization. Instead, TLR4 ligation enhanced both CD4(+) T-cell proliferation and survival in vitro. Using the experimental autoimmune encephalomyelitis (EAE) model, we found that the loss of TLR4 solely in CD4(+) T cells almost completely abrogated disease symptoms, mainly through blunted Th17 and, to a lesser degree, Th1 responses. Moreover, Tlr4(-/-) γδ T cells were defective in IL-17 and IFN-γ production following EAE induction. This study supports an important role of this innate receptor in the direct regulation of T-cell activation and survival during autoimmune inflammation.     

Measurements of immune responses for establishing correlates of vaccine protection against HIV

Well-defined correlates of protective immunity are an essential component of rational vaccine development. Despite years of basic science and three HIV vaccine efficacy trials, correlates of immunological protection from HIV infection remain undefined. In December 2010, a meeting of scientists engaged in basic and translational work toward developing HIV-1 vaccines was convened. The goal of this meeting was to discuss current opportunities and optimal approaches for defining correlates of protection, both for ongoing and future HIV-1 vaccine candidates; specific efforts were made to engage young scientists. We discuss here the highlights from the meeting regarding the progress made and the way forward for a protective HIV-1 vaccine.