Acid esophago-pharyngeal reflux as etiology of hoarseness

BACKGROUND: Gastroesophageal reflux has been implicated in otolaryngologic problems, particularly chronic hoarseness that cannot be attributed to other causes. PATIENTS AND METHODS: To study this relationship between gastroesophageal reflux and chronic hoarseness we used 24-h dual-site ambulatory pH-recordings in 68 patients with chronic hoarseness and laryngeal lesions suggestive of acid irritation. RESULTS: Thirty-eight patients (56%) had evidence of at least one esophago-pharyngeal reflux episode. The mean number of esophago-pharyngeal episodes was 6.7 +/- 12 within 24 hours (range: 1-34 episodes). The mean duration of these episodes was 201 +/- 28 seconds (range: 6 seconds-19.6 minutes). Most patients with esophago-pharyngeal reflux had no evidence of pathologic gastroesophageal reflux. Only 28.9% of the patients with esophago-pharyngeal reflux episodes also had pathologic gastroesophageal phageal reflux, whereas 23.3% of the patients without esophago-pharyngeal reflux had no gastroesophageal reflux disease. The esophago-pharyngeal reflux occurred mainly in the upright position. CONCLUSIONS: Occult esophago-pharyngeal reflux, predominantly in the upright position, appears to be common and severe in patients with chronic hoarseness. Gastroesophageal reflux may be an important factor in the pathogenesis of chronic hoarseness. The causative mechanisms are not clear.     

Maintenance of recombinant type A gamma-aminobutyric acid receptor function: role of protein tyrosine phosphorylation and calcineurin

In the present study, rundown of gamma-aminobutyric acid (GABA)-activated Cl- channels was studied in recombinant GABAA receptors stably expressed in human embryonic kidney cells (HEK 293), with conventional whole-cell and amphotericin B-perforated patch recording. When [ATP]i was lowered to 1 mM and resting [Ca++]i was buffered to a relatively high level, the response of alpha 3 beta 2 gamma 2 GABAA receptors to relatively low [GABA] (up to 50 microM) did not show rundown in the whole-cell configuration. However, high [GABA] (greater than 200 microM) induced significant rundown, which was observed by decreases in both the maximum GABA-induced current and GABA EC50. Rundown was prevented completely with a solution containing 4 mM Mg(++)-ATP and low resting [Ca++]i, or during perforated patch recording. The magnitude of rundown was comparable in alpha 1 beta 2 gamma 2 and beta 2 gamma 2 receptors. Neither stimulation nor inhibition of protein kinase A or protein kinase C had a significant effect on rundown. However, sodium metavanadate, an inhibitor of protein tyrosine phosphatase, significantly reduced rundown. In addition, inhibition of protein tyrosine kinase activity by either genistein or lavendustin A induced rundown of the GABA response. Inhibition of the Ca++/calmodulin-dependent phosphatase calcineurin with fenvalerate also prevented rundown of the response to GABA. Our results demonstrate that rundown of GABAA receptor function is concentration-dependent, due to depletion of ATP and/or unbuffered [Ca++]i, and does not depend on the presence or subtype of the alpha subunit. We propose that protein phosphorylation at a tyrosine kinase-dependent site, and a distinct unidentified site, which is dephosphorylated by calcineurin, maintains the function of GABAA receptors.     

Synthesis and in vitro antimalarial activity of sulfone endoperoxides

A series of 4,8-dimethyl-4-phenylsulfonylmethyl-2,3-dioxabicyclo[3.3.1]+ ++nonanes, carrying a variety of substituents at position-8 (4) were prepared by a short and efficient method from R-(+)-limonene. Key reactions include thiol oxygen cooxidation, and alkylation and acylation of a sterically hindered tertiary alcohol compatible with the endoperoxy functionality. Some of compounds 4, which are structurally related to yingzhaosu A (2), were found to exhibit in vitro antimalarial activity comparable to that of artemisinin (1) and superior to that of arteflene (3).     

A clinicopathologic study of mucinous gastric carcinoma including multivariate analysis

BACKGROUND: Mucinous gastric carcinoma (MGC) is a rare subtype of gastric adenocarcinoma, and its clinical and pathologic features are still controversial. To clarify the significance of this subtype of carcinoma, the authors conducted a case-control study to investigate the clinicopathologic characteristics of MGC and determine whether this mucin-producing histologic type is associated with a worse prognosis than other gastric carcinomas. METHODS: Twenty-two cases of MGC and 46 patients with nonmucinous gastric carcinoma (NGC) were included. Patients were evaluated on the basis of age, gender, tumor size, location, depth of tumor invasion, histologic differentiation, lymph node involvement, organ metastasis, stage at presentation, surgical curability, adjuvant chemotherapy and radiation therapy. To determine whether the MGC itself was an independent prognostic factor, a multivariate analysis was performed with the Cox proportional hazards model. RESULTS: The MGC patients were found to have larger tumors (P < 0.001), tumors more often located in the upper stomach (P < 0.05), more serosal invasion (P < 0.05), more lymph node involvement (P < 0.05), greater frequency of advanced stage disease (P < 0.01), and lower 5-year survival rates (P < 0.05) than NGC patients. There was no significant correlation between the subtypes of differentiation of MGC and other data, including the prognosis. Multivariate analysis showed that clinically important predictive factors were serosal invasion and disease stage at diagnosis. The mucinous histologic type itself was not an independent factor for poor prognosis. CONCLUSIONS: The overall survival rate for patients with MGC was worse than that for patients with NGC. The poor prognosis was correlated with more advanced stage at diagnosis and more frequent serosal invasion, not with the mucinous histologic type.     

Phospholipid membrane stabilization by dimethylsulfoxide and other inducers of Friend leukemic cell differentiation

A large number of low molecular weight polar cryoprotective agents have recently been found to induce erythroid differentiation of Friend leukemic cells in vitro. The effect of these agents on membrane fluidity in phospholipid vesicles was studied by determining the solid-to-liquid crystalline phase transition using differential scanning calorimetry. Some of the inducing agents studies were found to raise the normal transition temperature (Tc) by a few degrees. All of these agents were found to produce a separate transition at a much higher temperature. Changes in the head group of the phospholipid, the pH, the presence of divalent cations, and the addition of other membrane-active compounds were found to significantly influence the inducing agent's effects on the Tc of phospholipid membranes. The ability of the different agents to produce a new transition at a high temperature was found to correlate well with their ability to induce Friend leukemic cell differentiation. The possible mechansims of action of the chemical inducers, and the significance of the observed membrane effects on differentiation and malignancy are discussed. It is concluded that inducing agents decrease the fluidity and stabilize phospholipid membranes, and that their effects in cell differentiation might be initiated by a similar change in the properties of cell membranes.     

Interaction of non-histone chromosomal proteins HMG1 and HMG2 with DNA

Interaction between non-histone protein HMG1 or HMG2 and DNA has been studied by using thermal denaturation and circular dichroism (CD) spectroscopy. We have made the following observations. 1. The binding of each of these two proteins to DNA stabilizes the latter, as shown by an increase in melting temperature of 20 degrees C (from 45 degrees C to about 65 degrees C). 2. There are 6.0 amino acids/nucleotide in HMG1-bound DNA and 5.0 in HMGI-bound DNA which suggests that each HMB1 moleculae would cover about 20 base pairs of DNA and each HMG2 molecule would cover about 25 base pairs. 3. The alpha-helical content of these two non-histone proteins in the complexes, estimated from the CD value at 220 nm, is about one third to one half that of total proteins in calf thymus chromatin. 4. DNA conformation is distorted only slightly by the binding of protein HMG1 or HMG2. 5. Neither the melting nor the CD properties of HMG1-DNA or HMG2-DNA complexes differ substantially whether they are prepared by NaCl-gradient dialysis in urea or by direct mixing of protein and DNA at 0.15 M NaCl, followed by dialysis against the same buffer i.e. 0.25 mM EDTA (pH 8.0).