Robert L. Young

Papillary thyroid carcinoma: A 10 year foliow-up report of the impact of therapy in 576 patients

Data from 576 patients with papillary thyroid cancer were retrospectively analyzed. With a median follow-up of 10 years and three months, there were six deaths from, and 84 recurrences of, thyroid cancer. Of the latter, 16 (19 percent) could not be eradicated. Death from thyroid cancer occurred only in those 30 years of age or over at the time of diagnosis and only in patients with primary tumors larger than 1.5 cm in diameter. Locally invasive tumor was associated with a poor prognosis. Cervical lymph node metastases found at initial surgery were associated with higher recurrence rates but not higher mortality rates. Treatment with total thyroidectomy, postoperative radioiodine and thyroid hormone resulted in the lowest recurrence and mortality rates except in those patients with small primary tumors (less than 1.5 cm diameter) in whom less than total thyroidectomy and postoperative therapy with thyroid hormone alone gave results which did not differ statistically from those achieved with more aggressive therapy. No important differences in outcome were observed when cervical lymph node metastases were simply excised or more aggressively treated by neck dissection. External radiation and as initial adjunctive therapy adversely influenced outcome.

Neutrophil Extracellular Trap (NET)-Mediated Killing of Pseudomonas aeruginosa: Evidence of Acquired Resistance within the CF Airway, Independent of CFTR

The inability of neutrophils to eradicate Pseudomonas aeruginosa within the cystic fibrosis (CF) airway eventually results in chronic infection by the bacteria in nearly 80 percent of patients. Phagocytic killing of P. aeruginosa by CF neutrophils is impaired due to decreased cystic fibrosis transmembrane conductance regulator (CFTR) function and virulence factors acquired by the bacteria. Recently, neutrophil extracellular traps (NETs), extracellular structures composed of neutrophil chromatin complexed with granule contents, were identified as an alternative mechanism of pathogen killing. The hypothesis that NET-mediated killing of P. aeruginosa is impaired in the context of the CF airway was tested. P. aeruginosa induced NET formation by neutrophils from healthy donors in a bacterial density dependent fashion. When maintained in suspension through continuous rotation, P. aeruginosa became physically associated with NETs. Under these conditions, NETs were the predominant mechanism of killing, across a wide range of bacterial densities. Peripheral blood neutrophils isolated from CF patients demonstrated no impairment in NET formation or function against P. aeruginosa. However, isogenic clinical isolates of P. aeruginosa obtained from CF patients early and later in the course of infection demonstrated an acquired capacity to withstand NET-mediated killing in 8 of 9 isolates tested. This resistance correlated with development of the mucoid phenotype, but was not a direct result of the excess alginate production that is characteristic of mucoidy. Together, these results demonstrate that neutrophils can kill P. aeruginosa via NETs, and in vitro this response is most effective under non-stationary conditions with a low ratio of bacteria to neutrophils. NET-mediated killing is independent of CFTR function or bacterial opsonization. Failure of this response in the context of the CF airway may occur, in part, due to an acquired resistance against NET-mediated killing by CF strains of P. aeruginosa.

Painless Thyroiditis and Transient Hyperthyroidism Without Goiter

Eight women had painless thyroiditis, transient thyrotoxicosis, and low radioactive iodine uptakes but were without goiter; they constituted 15% of all thyrotoxicosis cases that we saw during the past year. Standard antithyroid antibody tests by tanned erythrocyte hemagglutination, complement fixation, and colloid and microsomal fluorescence, if present initally, were only weakly psotivie and became negative by 9 months. However, human antithyroglobulin antibody levels by a sensitive radioimmunoassay were elevated initially in all patients. In general, these radioimmunoassayable antibody levels fell, but they had not returned to normal by 9 months. Serial thyroid function tests and standard antithyroid antibody tests were most compatible with subactue thyroidtis. However, the persistence of radioimmunoassayable antithyroblobulin antibodies and recent reports of histologic evidence of lymphocyte thyroiditis in similar patients with goiter leaves open the possibility that this is a previously unrecognized presentation of chronic lymphocytic thyroiditis. Neither the cause nor the ultimate course of this syndrome is known.

Effects of Gender and Age at Diagnosis on Disease Progression in Long-term Survivors of Cystic Fibrosis

RATIONALE Long-term survivors of cystic fibrosis (CF) (age > 40 yr) are a growing population comprising both patients diagnosed with classic manifestations in childhood, and nonclassic phenotypes typically diagnosed as adults. Little is known concerning disease progression and outcomes in these cohorts. OBJECTIVES Examine effects of age at diagnosis and gender on disease progression, setting of care, response to treatment, and mortality in long-term survivors of CF. METHODS Retrospective analysis of the Colorado CF Database (1992-2008), CF Foundation Registry (1992-2007), and Multiple Cause of Death Index (1992-2005). MEASUREMENTS AND MAIN RESULTS Patients with CF diagnosed in childhood and who survive to age 40 years have more severe CFTR genotypes and phenotypes compared with adult-diagnosed patients. However, past the age of 40 years the rate of FEV(1) decline and death from respiratory complications were not different between these cohorts. Compared with males, childhood-diagnosed females were less likely to reach age 40 years, experienced faster FEV(1) declines, and no survival advantage. Females comprised the majority of adult-diagnosed patients, and demonstrated equal FEV(1) decline and longer survival than males, despite a later age at diagnosis. Most adult-diagnosed patients were not followed at CF centers, and with increasing age a smaller percentage of CF deaths appeared in the Cystic Fibrosis Foundation Registry. However, newly diagnosed adults demonstrated sustained FEV(1) improvement in response to CF center care. CONCLUSIONS For patients with CF older than 40 years, the adult diagnosis correlates with delayed but equally severe pulmonary disease. A gender-associated disadvantage remains for females diagnosed in childhood, but is not present for adult-diagnosed females.

Pulmonary Sarcoidosis: A Prospective Evaluation of Glucocorticoid Therapy

Abstract Glucocorticoid therapy has long been advocated for treatment of pulmonary dysfunction in sarcoidosis. No controlled prospective study in current medical literature establishes the efficacy...

Disruption of Contact Lens-Associated Pseudomonas aeruginosa Biofilms Formed in the Presence of Neutrophils

PURPOSE To evaluate the capacity of neutrophils to enhance biofilm formation on contact lenses by an infectious Pseudomonas aeruginosa (PA) corneal isolate. Agents that target F-actin and DNA were tested as a therapeutic strategy for disrupting biofilms formed in the setting of neutrophils in vitro and for limiting the infectious bioburden in vivo. METHODS Biofilm formation by infectious PA strain 6294 was assessed in the presence of neutrophils on a static biofilm plate and on unworn etafilcon A soft contact lenses. A d-isomer of poly(aspartic acid) was used alone and with DNase to reduce biofilm formation on test contact lenses. The gentamicin survival assay was used to determine the effectiveness of the test compound in reducing subsequent intracellular bacterial load in the corneal epithelium in a contact lens infection model in the rabbit. RESULTS In a static reactor and on hydrogel lenses, PA biofilm density was enhanced 30-fold at 24 hours in the presence of neutrophils (P < 0.0001). The combination of DNase and anionic poly(aspartic acid) reduced the PA biofilms formed in the presence of activated neutrophils by 79.2% on hydrogel contact lenses (P < 0.001). An identical treatment resulted in a 41% reduction in internalized PA in the rabbit corneal epithelium after 24 hours (P = 0.03). CONCLUSIONS These results demonstrate that PA can exploit the presence of neutrophils to form biofilm on contact lenses within a short time. Incorporation of F-actin and DNA represent a mechanism for neutrophil-induced biofilm enhancement and are targets for available agents to disrupt pathogenic biofilms formed on contact lenses and as a treatment for established corneal infections.

Potential of anti-inflammatory treatment for cystic fibrosis lung disease.

Cystic fibrosis (CF) is the most common life-shortening genetic disorder in Caucasians. With improved diagnosis and treatment, survival has steadily increased. Unfortunately, the overwhelming majority of patients still die from respiratory failure caused by structural damage resulting from airway obstruction, recurrent infection, and inflammation. Here, we discuss the role of inflammation and the development of anti-inflammatory therapies to treat CF lung disease. The inflammatory host response is the least addressed component of CF airway disease at this time. Current challenges in both preclinical and clinical investigation make the identification of suitable anti-inflammatory drugs more difficult. Despite this, many researchers are making significant progress toward this goal and the CF research community has reason to believe that new therapies will emerge from these efforts.

Glucose-Insulin Response to Oral Glucose in a Healthy Obese Population

The characteristics of the glucose and insulin responses during the glucose tolerance test (GTT) in obese people as a group have not been established. We analyzed glucose and insulin levels during GTT in 160 healthy obese patients who averaged 42% over ideal body weight. Statistical upper limit of normal for 2-h glucose was 260 mg/dl in women and 206 mg/dl in men. Although there was a significant correlation between insulin and glucose levels in both sexes and between insulin and degree of obesity in women, r values were relatively low (r < 0.4 for all). High insulin levels and delayed peak insulin were present in the majority of patients with normal GTT and absent in many of the most obese patients. Results indicate that upper limits of normal glucose for GTT in the obese are much higher than currently accepted criteria.

The treatment of benign thyroid disease

The treatment of benign forms of thyroid disease is reviewed. Endemic goiter is a public health problem preventable by the addition of iodine to the food or water supply. Endemic and familial goiters are treated with replacement doses of I-thyroxine, as are sporadic colloid goiters and goiters resulting from chronic thyroiditis. Hyperfunctioning autionomous nodules without thyrotoxicosis and cystic nodules require no specific therapy. Prophylaxis against diffuse or nodular goiter after radiation to the head or neck for therapeutic purposes with thyroxine replacement therapy is debatable. All forms of hypothyroidism, including incipient types, require replacement thyroxine therapy, but this should be undertaken cautiously in older patients and in those with evidence of ischemic myocardial disease. Myxedema coma requires vigorous treatment and detailed supervision because of dismal mortality rates. Iodine 131 is the treatment of choice in diffuse toxic goiter, but alternative forms.

Autoimmune Disease, Thyroiditis, and Hyperthyroidism Without Goiter

Excerpt To the editor: We previously described eight patients with a syndrome of painless thyroiditis and transient hyperthyroidism without goiter (1). All patients have followed the course of suba...