Citations

Purpose The Dynamic International Prognostic Scoring System (DIPSS) for primary myelofibrosis (PMF) uses five risk factors to predict survival: age older than 65 years, hemoglobin lower than 10 g/dL, leukocytes higher than 25 × 10 9 /L, circulating blasts ≥ 1%, and constitutional symptoms. The main objective of this study was to refine DIPSS by incorporating prognostic information from karyotype, platelet count, and transfusion status. Patients and Methods Mayo Clinic databases for PMF were used to identify patients with available bone marrow histologic and cytogenetic information. Results Seven hundred ninety-three consecutive patients were selected and divided into two groups based on whether or not their referral occurred within (n = 428; training set) or after (n = 365; test set) 1 year of diagnosis. Multivariable analysis identified DIPSS, unfavorable karyotype, platelets lower than 100 × 10 9 /L, and transfusion need as independent predictors of inferior survival. Hazard ratio (HR) –weighted adverse points were assigned to these variables to develop a composite prognostic model using the training set. The model was subsequently validated in the test set, and its application to all 793 patients resulted in median survivals of 185, 78, 35, and 16 months for low, intermediate-1 (HR, 2.2; 95% CI, 1.4 to 3.6), intermediate-2 (HR, 4.9; 95% CI, 3.2 to 7.7), and high-risk groups (HR, 10.7; 95% CI, 6.8 to 16.9), respectively (P < .001). Leukemia-free survival was predicted by the presence of thrombocytopenia or unfavorable karyotype (10-year risk of 31% v 12%; HR, 3.3; 95% CI, 1.9 to 5.6). Conclusion DIPSS plus effectively combines prognostic information from DIPSS, karyotype, platelet count, and transfusion status to predict overall survival in PMF. In addition, unfavorable karyotype or thrombocytopenia predicts inferior leukemia-free survival.

Cysts of the vallecula are rare, accounting for 10.5% to 20.1% of all laryngeal cysts. Vallecular cysts may present with diverse symptoms affecting the voice, airway, and swallowing. We describe the evaluation and treatment of a 70-year-old woman who presented with dysphagia caused by large bilateral vallecular cysts.

We previously reported that small mesenteric arteries from hypertensive rats have increased NOS-derived H2O2 and reduced NO/cGMP signaling. We hypothesized that antihypertensive therapy lowers blood pressure through a tetrahydrobiopterin (BH4)-dependent mechanism restoring NO/cGMP signaling and endothelial NOS (NOS3; eNOS) phosphorylation in small arteries. To test this hypothesis, small mesenteric arteries from normotensive rats (NORM), angiotensin II-infused rats (ANG), ANG rats with triple therapy (reserperine, hydrochlorothiazide, and hydralazine), or ANG rats with oral BH4 therapy were studied. Both triple therapy and oral BH4 therapy attenuated the rise in systolic blood pressure in ANG rats and restored NO/cGMP signaling in small arteries similarly. Triple therapy significantly increased vascular BH4 levels and BH4-to-BH2 ratio similar to ANG rats with BH4 supplementation. Furthermore, triple therapy (but not oral BH4 therapy) significantly increased GTP cyclohydrolase I (GTPCH I) activity in small arteries without a change in expression. NOS3 phosphorylation at Ser1177 was reduced in small arteries from ANG compared with NORM, while NOS3 phosphorylation at Ser633 and Thr495 were similar in ANG and NORM. NOS3 phosphorylation at Ser1177 was restored with triple therapy or oral BH4 in ANG rats. In conclusion, antihypertensive therapy regulates NO/cGMP signaling in small arteries through increasing BH4 levels and NOS3 phosphorylation at Ser1177.

Substance P is a neuropeptide released by afferent neurons in the respiratory tract during inflammatory reactions. It produces effects on blood vessels, bronchial smooth muscle, nasal glands, and respiratory cilia. We studied the in vitro effect of substance P on the ciliary beat frequency of human adenoid explants and its mechanism of action. Substance P was added to cultured adenoid at concentrations of 10−10, 10−8, 10−6, and 10−4 mol/L. Ciliary beat frequency was determined with phase‐contrast microscopy and microphotometry. Substance P increased ciliary beat frequency a maximum of 11.9% ± 3.8% (p < 0.01). Diclofenac (10−6 mol/L) significantly blocked the ciliostimulatory effects of SP (p < 0.022), indicating that prostaglandin synthesis is an intermediate step in the action of substance P on ciliary beat frequency. The L‐arginine analogs, NG‐nitro‐L‐arginine methyl ester and NG‐monomethyl‐L‐arginine, inhibit nitric oxide synthesis from L‐arginine. L‐Arginine analogs (10−4 to 10−2 mol/L) inhibited the effect of substance P (p < 0.02 at the higher concentration). This inhibition was reversed by adding L‐arginine, demonstrating that nitric oxide production is a required step in substance P‐induced ciliostimulation. Substance P stimulates ciliary activity in human nasal mucosa as a result of secondary production and release of endogenous prostaglandins and nitric oxide. It is likely that inflammatory disease processes that stimulate release of substance P and subsequent prostaglandin and nitric oxide production modify mucociliary transport. Pharmacologic modification of substance P and its second messengers may eventually permit regulation of this important defense mechanism and control of neurogenic inflammation.

It has been suggested that leukotrienes C4 (LTC4) and D4 (LTD4) released from upper respiratory mucosa influence mucociliary transport during allergic reactions. We studied the in vitro effects of leukotrienes C4 and D4 on the ciliary beat frequency (CBF) of human adenoid explants over a 5‐hour period. Tissue explants were cultured at 35° C in Minimum Essential Medium Eagle (MEM). The CBF was measured using phase contrast microscopy and microphotometry. Measurements of CBF were recorded in medium alone and in medium containing LTC4 or LTD4 at concentrations of 10−8 and 10−6 M. LTC4 and LTD4 increased CBF at concentrations of 10−8 and 10−6 M with increases of 20.51% ± 2.69% and 29.84% ± 4.06%, respectively. To determine the specificity of the LTC4 and LTD4 effects, the ciliated epithelium was treated with the specific leukotriene receptor antagonist LY‐171,883 before administration of LTC4 and LTD4. LY‐171,883 (10−6 M) significantly inhibited the ciliostimulatory effects of both leukotrienes. Our findings indicate that LTC4 and LTD4 increase CBF in vitro by activation of the LTD4 receptor.

Abstract The Task Force on Nomenclature was commissioned in 2007 by the Association for Applied Psychophysiology and Biofeedback, the Biofeedback Certification Institute of America, and the International Society for Neurofeedback and Research to develop an updated official definition of biofeedback. The article describes the task force participants and the process and publishes the task force's definition of biofeedback, which was approved by the three participating professional organizations.