External auditory canal cholesteatoma: reassessment of and amendments to its categorization, pathogenesis, and treatment in 34 patients

OBJECTIVE: External auditory canal cholesteatoma (EACC) is a rarity. Although there have been numerous case reports, there are only few systematic analyses of case series, and the pathogenesis of idiopathic EACC remains enigmatic. STUDY DESIGN: In a tertiary referral center for a population of 1.5 million inhabitants, 34 patients with 35 EACC (13 idiopathic [1 bilateral] and 22 secondary) who were treated between 1994 and 2006 were included in the study. RESULTS: EACC cardinal symptoms were longstanding otorrhea (65%) and dull otalgia (12%). Focal bone destruction in the external auditory canal with retained squamous debris and an intact tympanic membrane were characteristic. Only 27% of the patients showed conductive hearing loss exceeding 20 dB. Patients with idiopathic EACC had lesions typically located on the floor of the external auditory canal and were older, and the mean smoking intensity was also greater (p < 0.05) compared with patients with secondary EACC. The secondary lesions were assigned to categories (poststenotic [n = 6], postoperative [n = 6], and posttraumatic EACC [n = 4]) and rare categories (radiogenic [n = 2], postinflammatory [n = 1], and postobstructive EACC [n = 1]). In addition, we describe 2 patients with EACC secondary to the complete remission of a Langerhans cell histiocytosis of the external auditory canal. Thirty of 34 patients were treated surgically and became all free of recurrence, even after extensive disease. DISCUSSION: For the development of idiopathic EACC, repeated microtrauma (e.g., microtrauma resulting from cotton-tipped applicator abuse or from hearing aids) and diminished microcirculation (e.g., from smoking) might be risk factors. A location other than in the inferior portion of the external auditory canal indicates a secondary form of the disease, as in the case of 2 patients with atypically located EACC after years of complete remission of Langerhans cell histiocytosis, which we consider as a new posttumorous category and specific late complication of this rare disease.

Computational study of internal and external condensing flows and experimental synthesis to investigate their attainability and stability in ground-based and space-based environments

This doctoral thesis presents the computational work and synthesis with experiments for internal (tube and channel geometries) as well as external (flow of a pure vapor over a horizontal plate) condensing flows. The computational work obtains accurate numerical simulations of the full two dimensional governing equations for steady and unsteady condensing flows in gravity/0g environments. This doctoral work investigates flow features, flow regimes, attainability issues, stability issues, and responses to boundary fluctuations for condensing flows in different flow situations. This research finds new features of unsteady solutions of condensing flows; reveals interesting differences in gravity and shear driven situations; and discovers novel boundary condition sensitivities of shear driven internal condensing flows. Synthesis of computational and experimental results presented here for gravity driven in-tube flows lays framework for the future two-phase component analysis in any thermal system. It is shown for both gravity and shear driven internal condensing flows that steady governing equations have unique solutions for given inlet pressure, given inlet vapor mass flow rate, and fixed cooling method for condensing surface. But unsteady equations of shear driven internal condensing flows can yield different “quasi-steady” solutions based on different specifications of exit pressure (equivalently exit mass flow rate) concurrent to the inlet pressure specification. This thesis presents a novel categorization of internal condensing flows based on their sensitivity to concurrently applied boundary (inlet and exit) conditions. The computational investigations of an external shear driven flow of vapor condensing over a horizontal plate show limits of applicability of the analytical solution. Simulations for this external condensing flow discuss its stability issues and throw light on flow regime transitions because of ever-present bottom wall vibrations. It is identified that laminar to turbulent transition for these flows can get affected by ever present bottom wall vibrations. Detailed investigations of dynamic stability analysis of this shear driven external condensing flow result in the introduction of a new variable, which characterizes the ratio of strength of the underlying stabilizing attractor to that of destabilizing vibrations. Besides development of CFD tools and computational algorithms, direct application of research done for this thesis is in effective prediction and design of two-phase components in thermal systems used in different applications. Some of the important internal condensing flow results about sensitivities to boundary fluctuations are also expected to be applicable to flow boiling phenomenon. Novel flow sensitivities discovered through this research, if employed effectively after system level analysis, will result in the development of better control strategies in ground and space based two-phase thermal systems.

DEVELOPMENT OF A CONCEPTUAL MODEL AND PARAMETERIZATION OF A MATHEMATICAL MODEL FOR SEDIMENT PHOSPHORUS DIAGENESIS, SORPTION AND RELEASE FROM ONONDAGA LAKE SYRACUSE, NEW YORK

Eutrophication is a persistent problem in many fresh water lakes. Delay in lake recovery following reductions in external loading of phosphorus, the limiting nutrient in fresh water ecosystems, is often observed. Models have been created to assist with lake remediation efforts, however, the application of management tools to sediment diagenesis is often neglected due to conceptual and mathematical complexity. SED2K (Chapra et al. 2012) is proposed as a "middle way", offering engineering rigor while being accessible to users. An objective of this research is to further support the development and application SED2K for sediment phosphorus diagenesis and release to the water column of Onondaga Lake. Application of SED2K has been made to eutrophic Lake Alice in Minnesota. The more homogenous sediment characteristics of Lake Alice, compared with the industrially polluted sediment layers of Onondaga Lake, allowed for an invariant rate coefficient to be applied to describe first order decay kinetics of phosphorus. When a similar approach was attempted on Onondaga Lake an invariant rate coefficient failed to simulate the sediment phosphorus profile. Therefore, labile P was accounted for by progressive preservation after burial and a rate coefficient which gradual decreased with depth was applied. In this study, profile sediment samples were chemically extracted into five operationally-defined fractions: CaCO3-P, Fe/Al-P, Biogenic-P, Ca Mineral-P and Residual-P. Chemical fractionation data, from this study, showed that preservation is not the only mechanism by which phosphorus may be maintained in a non-reactive state in the profile. Sorption has been shown to contribute substantially to P burial within the profile. A new kinetic approach involving partitioning of P into process based fractions is applied here. Results from this approach indicate that labile P (Ca Mineral and Organic P) is contributing to internal P loading to Onondaga Lake, through diagenesis and diffusion to the water column, while the sorbed P fraction (Fe/Al-P and CaCO3-P) is remaining consistent. Sediment profile concentrations of labile and total phosphorus at time of deposition were also modeled and compared with current labile and total phosphorus, to quantify the extent to which remaining phosphorus which will continue to contribute to internal P loading and influence the trophic status of Onondaga Lake. Results presented here also allowed for estimation of the depth of the active sediment layer and the attendant response time as well as the sediment burden of labile P and associated efflux.

Motesanib diphosphate in progressive differentiated thyroid cancer

BACKGROUND: The expression of vascular endothelial growth factor (VEGF) is characteristic of differentiated thyroid cancer and is associated with aggressive tumor behavior and a poor clinical outcome. Motesanib diphosphate (AMG 706) is a novel oral inhibitor of VEGF receptors, platelet-derived growth-factor receptor, and KIT. METHODS: In an open-label, single-group, phase 2 study, we treated 93 patients who had progressive, locally advanced or metastatic, radioiodine-resistant differentiated thyroid cancer with 125 mg of motesanib diphosphate, administered orally once daily. The primary end point was an objective response as assessed by an independent radiographic review. Additional end points included the duration of the response, progression-free survival, safety, and changes in serum thyroglobulin concentration. RESULTS: Of the 93 patients, 57 (61%) had papillary thyroid carcinoma. The objective response rate was 14%. Stable disease was achieved in 67% of the patients, and stable disease was maintained for 24 weeks or longer in 35%; 8% had progressive disease as the best response. The Kaplan-Meier estimate of the median duration of the response was 32 weeks (the lower limit of the 95% confidence interval [CI] was 24; the upper limit could not be estimated because of an insufficient number of events); the estimate of median progression-free survival was 40 weeks (95% CI, 32 to 50). Among the 75 patients in whom thyroglobulin analysis was performed, 81% had decreased serum thyroglobulin concentrations during treatment, as compared with baseline levels. The most common treatment-related adverse events were diarrhea (in 59% of the patients), hypertension (56%), fatigue (46%), and weight loss (40%). CONCLUSIONS: Motesanib diphosphate can induce partial responses in patients with advanced or metastatic differentiated thyroid cancer that is progressive. (ClinicalTrials.gov number, NCT00121628.)

Measuring finger joint cartilage by ultrasound as a promising alternative to conventional radiograph imaging

OBJECTIVE: To evaluate the reliability and validity of a novel ultrasound (US) imaging method to measure metacarpophalangeal (MCP) and proximal interphalangeal (PIP) finger joint cartilage. METHODS: We examined 48 patients with rheumatoid arthritis (RA), 18 patients with osteoarthritis (OA), 24 patients with unclassified arthritis of the finger joints, and 34 healthy volunteers. The proximal cartilage layer of MCP and PIP joints for fingers 2-5 was bilaterally visualized from a posterior view, with joints in approximately 90 degrees flexion. Cartilage thickness was measured with integrated tools on static images. External validity was assessed by measuring radiologic joint space width (JSW) and a numeric joint space narrowing (JSN) score in patients with RA. RESULTS: Precise measurement was possible for 97.5% of MCP and 94.2% of PIP joints. Intraclass correlation coefficients for bilateral total joint US scores were 0.844 (95% confidence interval [95% CI] 0.648-0.935) for interobserver comparisons and 0.928 (95% CI 0.826-0.971) for intraobserver comparisons (using different US devices). The US score correlated with JSN for both hands (adjusted R(2) = 0.513, P < 0.001) and JSW of the same finger joints (adjusted R(2) = 0.635, P < 0.001). Reduced cartilage shown by US allowed discrimination of early symptomatic OA versus early RA and healthy joints. In patients with RA, US scores correlated with duration of treatment-resistant, progressive RA. CONCLUSION: The US method of direct visualization and quantification of cartilage in MCP and PIP joints is objective, reliable, valid, and can be useful for diagnostic purposes in patients with arthritis.

Incidence and outcome of progressive multifocal leukoencephalopathy over 20 years of the Swiss HIV Cohort Study

BACKGROUND: We investigated the incidence and outcome of progressive multifocal leukoencephalopathy (PML) in human immunodeficiency virus (HIV)-infected individuals before and after the introduction of combination antiretroviral therapy (cART) in 1996. METHODS: From 1988 through 2007, 226 cases of PML were reported to the Swiss HIV Cohort Study. By chart review, we confirmed 186 cases and recorded all-cause and PML-attributable mortality. For the survival analysis, 25 patients with postmortem diagnosis and 2 without CD4+ T cell counts were excluded, leaving a total of 159 patients (89 before 1996 and 70 during 1996-2007). RESULTS: The incidence rate of PML decreased from 0.24 cases per 100 patient-years (PY; 95% confidence interval [CI], 0.20-0.29 cases per 100 PY) before 1996 to 0.06 cases per 100 PY (95% CI, 0.04-0.10 cases per 100 PY) from 1996 onward. Patients who received a diagnosis before 1996 had a higher frequency of prior acquired immunodeficiency syndrome-defining conditions (P = .007) but similar CD4+ T cell counts (60 vs. 71 cells/microL; P = .25), compared with patients who received a diagnosis during 1996 or thereafter. The median time to PML-attributable death was 71 days (interquartile range, 44-140 days), compared with 90 days (interquartile range, 54-313 days) for all-cause mortality. The PML-attributable 1-year mortality rate decreased from 82.3 cases per 100 PY (95% CI, 58.8-115.1 cases per 100 PY) during the pre-cART era to 37.6 cases per 100 PY (95% CI, 23.4.-60.5 cases per 100 PY) during the cART era. In multivariate models, cART was the only factor associated with lower PML-attributable mortality (hazard ratio, 0.18; 95% CI, 0.07-0.50; P < .001), whereas all-cause mortality was associated with baseline CD4+ T cell count (hazard ratio per increase of 100 cells/microL, 0.52; 95% CI, 0.32-0.85; P = .010) and cART use (hazard ratio, 0.37; 95% CI, 0.19-0.75; P = .006). CONCLUSIONS: cART reduced the incidence and PML-attributable 1-year mortality, regardless of baseline CD4+ T cell count, whereas overall mortality was dependent on cART use and baseline CD4+ T cell count.

JC virus-specific immune responses in human immunodeficiency virus type 1 patients with progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a frequently fatal disease caused by uncontrolled polyomavirus JC (JCV) in severely immunodeficient patients. We investigated the JCV-specific cellular and humoral immunity in the Swiss HIV Cohort Study. We identified PML cases (n = 29), as well as three matched controls per case (n = 87), with prospectively cryopreserved peripheral blood mononuclear cells and plasma at diagnosis. Nested controls were matched according to age, gender, CD4(+) T-cell count, and decline. Survivors (n = 18) were defined as being alive for >1 year after diagnosis. Using gamma interferon enzyme-linked immunospot assays, we found that JCV-specific T-cell responses were lower in nonsurvivors than in their matched controls (P = 0.08), which was highly significant for laboratory- and histologically confirmed PML cases (P = 0.004). No difference was found between PML survivors and controls or for cytomegalovirus-specific T-cell responses. PML survivors showed significant increases in JCV-specific T cells (P = 0.04) and immunoglobulin G (IgG) responses (P = 0.005). IgG responses in survivors were positively correlated with CD4(+) T-cell counts (P = 0.049) and negatively with human immunodeficiency virus RNA loads (P = 0.03). We conclude that PML nonsurvivors had selectively impaired JCV-specific T-cell responses compared to CD4(+) T-cell-matched controls and failed to mount JCV-specific antibody responses. JCV-specific T-cell and IgG responses may serve as prognostic markers for patients at risk.