Value of repeat endoscopic ultrasound-guided fine needle aspiration for suspected pancreatic cancer

Background and Aims: Endoscopic ultrasound‐guided fine needle aspiration (EUS‐FNA) is a safe and accurate technique for diagnosing pancreatic cancer. The value of repeat EUS‐FNA in patients with high clinical suspicion for pancreatic cancer after an inconclusive index study is unknown. Our aims were to determine the yield and success of repeat EUS‐FNA and the reasons for failure of initial EUS‐FNA. Methods: This was a retrospective analysis of prospectively collected data in a tertiary University based referral center for pancreatico‐biliary disorders. All patients who underwent more then one EUS‐FNA for evaluation of suspected pancreatic cancer over a five and a half year period were included in this analysis. Results: Of the 547 procedures performed on 517 patients, 24 (4.6%) patients underwent 51 repeat EUS‐FNA procedures. Initial EUS‐FNA was atypical/suspicious in 10 (41.6%), benign in 10 (41.6%), malignant in two (8.3%), and failed/indeterminate in two (8.3%) patients. Eight of 10 (80%) patients with atypical/suspicious findings at initial EUS‐FNA were diagnosed with malignancy on repeat EUS‐FNA. Of the 10 patients with benign findings at initial EUS‐FNA, repeat study diagnosed two (20%) with malignancy and the rest were confirmed benign on long‐term follow up (average 530 days, SD 369 days). Of the two patients with indeterminate findings at initial EUS‐FNA, repeat study diagnosed one patient with malignant disease and the other with benign disease that was confirmed by long‐term follow up. Of the two patients diagnosed with neoplastic disease at initial EUS‐FNA, repeat EUS‐FNA with immunostains downgraded both to chronic pancreatitis. Repeat EUS‐FNA facilitated determination of the true status of disease in 20 of 24 patients (accuracy 84%). Suspected reasons for failed initial EUS‐FNA were: coexisting pancreatitis (n = 10; 42%), technical difficulty due to scope positioning in uncinate lesion/sedation failure (n = 4; 16.7%), difficult cytology (partly cystic, extensive necrosis, well‐differentiated adenocarcinoma) (n = 4; 16.7%), presence of ascites or collaterals (n = 3; 12.5%), pathologist's interobserver variation (n = 2; 8.33%), and unknown reason in one patient. Conclusion: Repeat EUS‐FNA is warranted in patients with high clinical suspicion for pancreatic cancer despite indeterminate or negative findings at initial EUS‐FNA.     

Syndromic colon cancer: lynch syndrome and familial adenomatous polyposis

Colon cancer, the third leading cause of mortality from cancer in the United States, afflicts about 150,000 patients annually. More than 10% of these patients exhibit familial clustering. The most common and well characterized of these familial colon cancer syndromes is hereditary nonpolyposis colon cancer syndrome (Lynch syndrome), which accounts for about 2% to 3% of all cases of colon cancer in the United States. We review the current knowledge of familial cancer syndromes, with an emphasis on Lynch syndrome and familial adenomatous polyposis.     

Nitric oxide synthase inhibition promotes endothelium-dependent vasodilatation and the antihypertensive effect of L-serine

L-serine is a precursor of central neurotransmitters. Its cardiovascular effects are largely unstudied. We compared the in vitro effects of L-serine and acetylcholine in phenylephrine-constricted third-order branches of mesenteric arterioles in the NO synthase inhibitor N(G)-nitro L-arginine methyl ester (L-NAME), pretreated hypertensive rats, and a control group of normotensive male Sprague-Dawley rats. The changes in mean arterial pressure and heart rate evoked by acute intravenous infusion of either L-serine (0.1 to 3.0 mmol/kg) or acetylcholine (0.1 to 10.0 nmol/kg) were determined in anesthetized rats. L-serine evoked concentration-dependent (10 to 200 micromol/L) vasodilatation in endothelium-intact but not in endothelium-denuded vessels. It was abolished by the inclusion of a combination of apamin (SK(Ca) channel inhibitor) and TRAM-34 (IK(Ca) channel inhibitor) or ouabain (Na(+) pump inhibitor) and Ba(2+) (K(ir) channel inhibitor) or when the vessels were constricted by potassium chloride. The maximal response to L-serine was higher in the L-NAME treatment group (control 20% versus L-NAME 40%) in relation to the maximal response to acetylcholine (control 93% versus L-NAME 79%). L-serine evoked a rapid, reversible, dose-dependent fall in mean arterial pressure without increasing heart rate and was more pronounced in L-NAME-treated rats (maximal response: >60 mm Hg) than in the control rats (maximal response: 25 mm Hg). This was inhibited (P<0.01) by apamin+charybdotoxin pretreatment. The in vitro and in vivo data confirm that L-serine promotes vasodilatation in resistance arterioles and evokes a greater fall in mean arterial pressure in NO synthase-inhibited hypertensive rats via activation of apamin and charybdotoxin/TRAM-34-sensitive K(Ca) channels present on the endothelium.     

Purified and surfactant-free coenzyme Q10-loaded biodegradable nanoparticles

The intent of this work was to synthesize and comprehensively characterize ubiquinone-loaded, surfactant-free biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles in vitro. Surfactant-free, empty and ubiquinone (CoQ10)-loaded biodegradable nanoparticles were synthesized by nanoprecipitation, and the physicochemical properties of these nanoparticles were analyzed with a variety of techniques. Nanoprecipitation consistently yielded individual, sub-200nm, surfactant-free empty and CoQ10-loaded nanoparticles, where the physical and drug encapsulation characteristics were controlled by varying the formulation parameters. CoQ10 release was sustained for 2 weeks but then plateaued before 100% CoQ10 release. A novel, nondestructive purification protocol involving transient sodium dodecyl sulfate (SDS) adsorption to nanoparticles followed by centrifugation and dialysis was developed to yield purified, surfactant-free, CoQ10-loaded nanoparticles. This protocol permitted removal of unencapsulated CoQ10, prevented centrifugation-induced nanoparticle aggregation and preserved the surfactant-free and drug encapsulation properties of the nanoparticles. These CoQ10-loaded nanoparticles are promising as sustained drug delivery devices due to their extended CoQ10 release. Importantly, a surfactant-free nanoprecipitation procedure is presented that in combination with a novel purification step enables the synthesis of individual and purified CoQ10-loaded nanoparticles.     

Tryptophan mutations at azi-etomidate photo-incorporation sites on alpha1 or beta2 subunits enhance GABAA receptor gating and reduce etomidate modulation

The potent general anesthetic etomidate produces its effects by enhancing GABA(A) receptor activation. Its photolabel analog [(3)H]azi-etomidate labels residues within transmembrane domains on alpha and beta subunits: alphaMet236 and betaMet286. We hypothesized that these methionines contribute to etomidate sites formed at alpha-beta subunit interfaces and that increasing side-chain bulk and hydrophobicity at either locus would mimic etomidate binding and block etomidate effects. Channel activity was electrophysiologically quantified in alpha(1)beta(2)gamma(2L) receptors with alpha(1)M236W or beta(2)M286W mutations, in both the absence and the presence of etomidate. Measurements included spontaneous activation, GABA EC(50), etomidate agonist potentiation, etomidate direct activation, and rapid macrocurrent kinetics. Both alpha(1)M236W and beta(2)M286W mutations induced spontaneous channel opening, lowered GABA EC(50), increased maximal GABA efficacy, and slowed current deactivation, mimicking effects of etomidate on alpha(1)beta(2)gamma(2L) channels. These changes were larger with alpha(1)M236W than with beta(2)M286W. Etomidate (3.2 muM) reduced GABA EC(50) much less in alpha(1)M236Wbeta(2)gamma(2L) receptors (2-fold) than in wild type (23-fold). However, etomidate was more potent and efficacious in directly activating alpha(1)M236Wbeta(2)gamma(2L) compared with wild type. In alpha(1)beta(2)M286Wgamma(2L) receptors, etomidate induced neither agonist-potentiation nor direct channel activation. These results support the hypothesis that alpha(1)Met236 and beta(2)Met286 are within etomidate sites that allosterically link to channel gating. Although alpha(1)M236W produced the larger impact on channel gating, beta(2)M286W produced more profound changes in etomidate sensitivity, suggesting a dominant role in drug binding. Furthermore, quantitative mechanistic analysis demonstrated that wild-type and mutant results are consistent with the presence of only one class of etomidate sites mediating both agonist potentiation and direct activation.     

The Measurement of Spray Quality for Pan Coating Processes

In this study, we describe the use of an innovative imaging system to measure and control the effect of nozzle operating parameters on the characteristics of a spray. These characteristics, including spray pattern, droplet size distribution, and droplet velocity, define the quality of the spray. They can have significant impact on the efficiency of the pan coating process and the quality of the coat. Suspensions of different composition were used in this study, and the authors demonstrated that the spray characteristics can be controlled with this approach. The main conclusions from this study were:

Acute Posterior Multifocal Placoid Pigment Epitheliopathy Following Dengue Fever: A New Association for an Old Disease

Purpose: An association between antecedent viral illness and acute posterior multifocal placoid pigment epitheliopathy (APMPPE) has long been suspected. The authors propose dengue fever as a possible cause of APMPPE, based on three patients who travelled to or lived in endemic areas and had serologic evidence of prior exposure.

Methods: Review of case records of two patients.

Results: The index patient presented with APMPPE after her second confirmed dengue infection. A second patient with positive serology for dengue was subsequently identified, who had acute onset of posterior uveitis with APMPPE-like features. Dengue antibody titers were positive in both patients.

Conclusions: APMPPE may be another manifestation of dengue fever. Ophthalmologists should take travel histories and consider ordering dengue serology in appropriate patients with APMPPE even if fever is absent, and especially in patients with the possibility of attenuated systemic disease and a primarily immunologic reaction to subsequent exposure.