Citations

ObjectiveTo investigate the manofluorographic and functional outcomes after endoscopic laser cricopharyngeal myotomy (ELCPM) for cricopharyngeal (CP) bar.Study DesignCase series with chart review.SettingAcademic medical center.Subjects and MethodsReview of patients undergoing ELCPM between 2001 and 2007 was undertaken to determine the demographic, clinical, and manofluorographic findings before and six months after surgery. Two groups were established according to pharyngeal driving pressures: normal pressure group (> 55 mm Hg) and low pressure group (< 55 mm Hg).ResultsFourteen patients underwent ELCPM for CP bar without a concomitant head and neck or Zenker's procedure. There were no major surgical complications. All 14 patients improved at least one stage on the Functional Outcome Swallowing Scale (FOSS) after surgery. There was a statistically significant decrease in the FOSS stages after surgery. Videofluoroscopy demonstrated a significant postoperative increase in the mean cross‐sectional CP opening (CP‐area) from 32.75 to 123.52 mm2. Manofluorographic pressure recordings showed a significant postoperative decrease in the intrabolus pressure gradient across the cricopharyngeal region (IB‐Gra) from 25.44 to 13.22 mm Hg. Despite significant overall results, the change in the IB‐Gra showed no difference between the patient groups.ConclusionSubjective (FOSS) and objective manofluorographic (CP‐area, IB‐Gra) improvement in CP bar patients occurred after ELCPM. We suggest IB‐Gra as a reliable objective indicator for patients who might benefit from ELCPM and as an appropriate parameter for follow‐up after surgery. However, continued research on a larger patient population is required to enhance our understanding of CP bar and predictors of outcome after treatment of CP bar dysphagia.

Pituitary ACTH drives adrenal glucocorticoid (cortisol) pulses via a time-delayed asymptotic dose-response process. To test the postulate that ACTH stimulates cortisol secretion dynamically (unequally during the initiation and termination of a cortisol secretory burst), a mathematical formalism was developed in which dose-response hysteretic shifts were allowed, but not required, within the time evolution of ACTH-cortisol pulse pairs. A dual-waveform deconvolution model was used to quantify cortisol secretion rates and reconstruct ACTH concentration profiles in 28 healthy adults previously sampled every 10 min for 24 h in the unstressed state (8,120 measurements). ACTH concentration-cortisol secretion dose-response functions were then estimated in each subject 1) without hysteresis (base model) and with allowances for possible hysteresis in 2) ACTH potency, 3) adrenal sensitivity, and 4) ACTH efficacy. Model residual error was 40% lower in the potency and sensitivity models and 20% lower in the efficacy model than in the base model ( P < 0.001). Mean time shifts for inferable hysteretic inflection were model-independent, i.e., grand mean (95% confidence interval) 22 (12–39) min after the onset of a cortisol secretory burst. Half-maximally effective ACTH concentrations (EC50) differed before and after hysteretic inflection within individual pulses: 1) 9.4 and 54 ng/l in the potency model ( P < 0.001) and 2) 8.9 and 123 ng/l in the sensitivity model ( P < 0.001) compared with 16 ng/l in the no-hysteresis model ( P < 0.001). In the efficacy-shift model, estimated maximal ACTH drive varied by 17-fold within cortisol secretory bursts (from 22 to 1.3 nmol·l−1·min cortisol secretion−1, P < 0.001). The collective results introduce the basis for modeling the dynamics of rapid, reversible physiological downregulation within the span of single interpulse intervals in vivo. This construct should have utility in parsing mechanisms of physiological regulation in other integrative systems.

Introduction: Nummular headache is a rare primary headache disorder described by a focal circumscribed area of pain (2–6 cm in diameter). Literature on this disorder is sparse. Patients and methods: Here, we describe a case series of 16 patients (6 men, 10 women) seen at the Mayo Clinic. Results: Mean age of onset was 50 years (range, 19–79 years) and mean duration of headache was 7.9 years (range, 0.33–40 years). Location of headache varied and was found to be an average of 3.9 cm in diameter (range, 2–10 cm). Headache was episodic (<15 days/month) in four patients and chronic (>15 days/month) in 12 patients. Attention was paid to therapeutic interventions. Resolution was seen in 38% of patients. Migraine was present in the history of 56% of patients and medication overuse headache was found in 25%. Conclusions: Our series results support previous findings. In our population, no specific therapy was identified to be effective in more than one patient.

The family B G protein-coupled glucagon-like peptide 1 (GLP-1) receptor is an important drug target for treatment of type 2 diabetes. Like other family members, the GLP-1 receptor is a glycosylated membrane protein that contains three potential sites for N-linked glycosylation within the functionally important extracellular amino-terminal domain. However, the roles for each potential site of glycosylation in receptor biosynthesis, trafficking, and function are not known. In this work, we demonstrated that tunicamycin inhibition of glycosylation of the GLP-1 receptor expressed in CHO cells interfered with biosynthesis and intracellular trafficking, thereby eliminating natural ligand binding. To further investigate the roles of each of the glycosylation sites, site-directed mutagenesis was performed to eliminate these sites individually and in aggregate. Our results showed that mutation of each of the glycosylation sites individually did not interfere with receptor expression on the cell surface, ligand binding, and biological activity. However, simultaneous mutation of two or three glycosylation sites resulted in almost complete loss of GLP-1 binding and severely impaired biological activity. Immunostaining studies demonstrated receptor biosynthesis but aberrant trafficking, with most of the receptor trapped in the endoplasmic reticulum and golgi compartments and little of the receptor expressed on the cell surface. Interestingly, surface expression, ligand binding, and biological activity of these mutants improved significantly when biosynthesis was slowed using low temperature (30°C). These data suggest that N-linked glycosylation of the GLP-1 receptor is important for its normal folding and trafficking to the cell surface.