Citations

Objectives: The histopathologic origin of iatrogenic subglottic tracheal stenosis (ISTS) remains unclear. The purpose of this study was to use detailed operative microscopy to systematically examine the operative en bloc specimens of patients with ISTS and to observe the histologic and morphological changes in the hopes that these observations will provide insight into the histopathologic origin of these devastating injuries. Methods: The operative specimens of 18 patients who underwent open tracheal or laryngotracheal resection for ISTS were examined. Precise morphological characteristics were investigated for each tissue layer, including the adventitia, the outer surface of the perichondrium, the cartilage, the inner surface of the perichondrium, the submucosa, and the mucosa. Each tissue layer was evaluated independently and in relationship to the other layers. The cartilaginous airway was further evaluated relative to the pars membranacea. Results: The most common morphological finding in the epithelium was squamous metaplasia with occasional intense inflammation visible in the underlying mucosa, including cicatrization. The underlying cartilage demonstrated ossific metaplasia with sequestration in many cases. By far the most pronounced changes were found in the outer perichondrium and overlying adventitia and included diffuse paucicellular or hyperplastic fibrosis with intense hyperplastic scar formation or hyaline cicatrization. In the pars membranacea, severe scar formation and hyperplastic fibrosis were predominant. Ossific metaplasia was particularly severe in the lateral or outer parts of the tracheal ring, particularly in the vicinity of the adventitia and outer perichondrium. These changes were much more pronounced than the relatively minor changes observed in the submucosa and mucosa. Conclusions: The most severe pathologic observations occurred in the lateral tissue layers, ie, the outer perichondrium and adventia. Given that an injury occurs from the tracheal lumen, these tissue layers have the greatest distance from the site of injury. As only minor changes occurred in the inner tissue layers, we hypothesize that these tissues have a greater regenerative capacity than the outer layers. This study supports the theory that the depth of the airway injury is more critical to the development of ISTS than is the extent or length of the injury.

How sex steroids modulate glucocorticoid feedback on the hypothalamic-pituitary-corticotrope (HPC) unit is controversial in humans. We postulated that testosterone (T) in men and estradiol (E2) in women govern unstressed cortisol-mediated negative feedback on ACTH secretion. To test this hypothesis, 24 men and 24 women age 58 ± 2.4 yr were pretreated with leuprolide and either sex steroid (E2 in women, T in men) or placebo addback. Placebo or ketoconazole (KTCZ) was administered overnight to inhibit adrenal steroidogenesis during overnight 14-h intravenous infusions of saline or cortisol in a continuous versus pulsatile manner to test for feedback differences. ACTH was measured every 10 min during the last 8 h of the infusions. The main outcome measures were mean ACTH concentrations, pulsatile ACTH secretion, and ACTH approximate entropy (ApEn). ACTH concentrations were lower in women than men ( P < 0.01), and in women in the E2+ compared with E2− group under both continuous ( P = 0.01) and pulsatile ( P = 0.006) cortisol feedback, despite higher cortisol binding globulin and lower free cortisol levels in women than men ( P < 0.01). In the combined groups, under both modes of cortisol addback, ACTH concentrations, pulsatile ACTH secretion, and ACTH secretory-burst mass correlated negatively and univariately with E2 levels (each P < 0.005). E2 also suppressed ACTH ApEn (process randomness) during continuous cortisol feedback ( P = 0.004). T had no univariate effect but was a positive correlate of ACTH when assessed jointly with E2 (negative) under cortisol pulses. In conclusion, sex steroids modulate selective gender-related hypothalamic-pituitary adrenal-axis adaptations to cortisol feedback in unstressed humans.

OBJECTIVE While metformin is generally accepted as the first-line agent in treatment of type 2 diabetes, there are insufficient evidence and extensive debate about the best second-line agent. We aimed to assess the benefits and harms of four commonly used antihyperglycemia treatment regimens considering clinical effectiveness, quality of life, and cost. RESEARCH DESIGN AND METHODS We developed and validated a new population-based glycemic control Markov model that simulates natural variation in HbA1c progression. The model was calibrated using a U.S. data set of privately insured individuals diagnosed with type 2 diabetes. We compared treatment intensification of metformin monotherapy with sulfonylurea, dipeptidyl peptidase-4 inhibitor, glucagon-like peptide-1 receptor agonist, or insulin. Outcome measures included life-years (LYs), quality-adjusted life-years (QALYs), mean time to insulin dependence, and expected medication cost per QALY from diagnosis to first diabetes complication (ischemic heart disease, myocardial infarction, congestive heart failure, stroke, blindness, renal failure, amputation) or death. RESULTS According to our model, all regimens resulted in similar LYs and QALYs regardless of glycemic control goal, but the regimen with sulfonylurea incurred significantly lower cost per QALY and resulted in the longest time to insulin dependence. An HbA1c goal of 7% (53 mmol/mol) produced higher QALYs compared with a goal of 8% (64 mmol/mol) for all regimens. CONCLUSIONS Use of sulfonylurea as second-line therapy for type 2 diabetes generated glycemic control and QALYs comparable with those associated with other agents but at lower cost. A model that incorporates HbA1c and diabetes complications can serve as a useful clinical decision tool for selection of treatment options.

Objective To evaluate the relationship between partial nephrectomy ( PN ) and hospital availability of robot‐assisted surgery from a population‐based cohort in the USA . Methods After merging the Nationwide Inpatient Sample ( NIS ) and the A merican Hospital Association survey from 2006 to 2008, we identified 21 179 patients who underwent either PN or radical nephrectomy ( RN ) for renal cell carcinoma ( RCC ). The primary outcome assessed was the type of nephrectomy performed. Multivariable logistic regression identified the patient and hospital characteristics associated with receipt of PN . Results We identified 4832 (22.8%) and 16 347 (77.2%) patients who were treated for RCC with PN and RN , respectively. On multivariable analysis, patients were more likely to receive PN at academic centres (odds ratio [ OR ] 2.77; P < 0.001), urban centres ( OR 3.66; P < 0.001) and A merican College of Surgeons ( ACOS )‐designated cancer centres ( OR : 1.10; P < 0.05) compared with non‐academic, rural and non‐ ACOS ‐designated cancer centre hospitals, respectively. Robot‐assisted surgery availability at a hospital was also associated with a higher adjusted odds of PN compared with centres without that availability ( OR 1.28; P < 0.001). Conclusions Although academic and urban locations are establi s hed factors that affect the receipt of PN for RCC , the availability of robot‐assisted surgery at a hospital was also independently associated with higher use of PN . Our results are informative in identifying other key hospital characteristics which may facilitate greater adoption of PN .

SummaryMedically refractory epilepsy remains a major medical problem worldwide. Although some patients are eligible for surgical resection of seizure foci, a proportion of patients are ineligible for a variety of reasons. One such reason is that the foci reside in eloquent cortex of the brain and therefore resection would result in significant morbidity. This retrospective study reports our experience with a novel neurostimulation technique for the treatment of these patients. We identified three patients who were ineligible for surgical resection of the intracranially identified seizure focus because it resided in eloquent cortex, who underwent therapeutic trial of focal cortical stimulation delivered through the subdural monitoring grid. All three patients had a significant reduction in seizures, and two went on to permanent implantation, which resulted in long‐term reduction in seizure frequency. In conclusion, this small case report provides some evidence of proof of concept of the role of targeted continuous neocortical neurostimulation in the treatment of medically refractory focal epilepsy, and provides support for ongoing investigations into this treatment modality.A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

We assessed the in vitro activity of Manuka honey against biofilm bacteria in combination with antibiotics and visualized the effect of Manuka honey on bacterial biofilms using scanning electron microscopy. The fractional biofilm eradication concentration ( ∑ FBEC ) index for vancomycin plus Manuka honey against S. aureus IDRL-4284 biofilms was 0.34, indicating a synergistic interaction. The ∑ FBEC index for gentamicin plus Manuka honey against P. aeruginosa PAO1 biofilms was 0.78–0.82, indicating an additive interaction. Scanning electron microscopy of S. aureus IDRL-4284 and P. aeruginosa PAO1 biofilms exposed to Manuka honey and artificial honey containing the same sugar composition as Manuka honey showed that the former had more pronounced effects than the latter on both S. aureus and P. aeruginosa biofilms. Visualized effects included distorted cell morphologies for both bacteria and a decrease in P. aeruginosa extracellular matrix. In conclusion, Manuka honey has a synergistic interaction with vancomycin against S. aureus biofilms and an additive interaction with gentamicin against P. aeruginosa biofilms.

ABSTRACTBackgroundWe have reported that intermediate repeat lengths of the C9ORF72 repeat are a risk factor for Parkinson's disease (PD) in a clinically diagnosed data set. Because 10% to 25% of clinically diagnosed PD have different diagnoses upon autopsy, we hypothesized that this may reflect phenotypic heterogeneity or concomitant pathology of other neurodegenerative disorders.MethodsWe screened 488 autopsy‐confirmed PD cases for expansion haplotype tag rs3849942T. In 196 identified haplotype carriers, the C9ORF72 repeat was genotyped using the repeat‐primed polymerase chain reaction assay.ResultsNo larger (intermediate or expanded) repeats were found in these autopsy‐confirmed PD samples. This absence of larger repeats is significantly different from the frequency in clinically diagnosed datasets (P = 0.002).ConclusionsOur results suggest that expanded or intermediate C9ORF72 repeats in clinically diagnosed PD or parkinsonism might be an indication of heterogeneity in clinically diagnosed PD cases. Further studies are needed to elucidate the potential contribution of the C9ORF72 repeat to autopsy‐confirmed PD. © 2014 International Parkinson and Movement Disorder Society

AbstractBackgroundAsthma guidelines suggest reducing controller medications when asthma is stable.MethodsThe purpose of the study is to estimate the risk of asthma exacerbation in stable asthmatics who reduce inhaled corticosteroids (ICS) compared to those who maintain a stable ICS dose. We identified articles from a systematic review of English and non‐English articles using MEDLINE, EMBASE, Web of Science, and CENTRAL (inception to May 25, 2013). We included randomized controlled trials (RCTs) with a stable asthma run‐in period of 4 weeks or more, an intervention to reduce ICS, and a follow‐up period of at least 3 months.ResultsThe search strategy identified 2253 potential articles, of which 206 were reviewed at the full‐text level and 6 met criteria for inclusion. The relative risk of an asthma exacerbation in individuals who reduced ICS compared to those who maintained the same ICS dose was 1.25 (95% CI 0.96, 1.62; P = 0.10; I2 = 0%) in studies with a mean follow‐up of 22 weeks. Individuals who reduced ICS had a decreased% predicted FEV1 of 0.87% (95% CI −1.58%,3.33%; P = 0.49, I2 = 58%) and a decreased mean morning peak expiratory flow of 9.57 l/min (95% CI 1.25, 17.90; P = 0.02; I2 = 74%) compared to those individuals who maintained a stable ICS dose.ConclusionsAsthma exacerbations were statistically no more likely among individuals who reduced ICS compared to those who maintained their ICS dose, supporting current guidelines which recommend decreasing ICS by 50% after a period of asthma stability.