48-Hour pH Monitoring Increases the Risk of False Positive Studies When the Capsule is Prematurely Passed

Ambulatory wireless 48-h esophageal pH monitoring (Bravo Medtronic, Shoreview, MN, USA) has been shown to be more sensitive in detecting abnormal esophageal acid exposure compared with transnasal 24-h pH probes. However, accurate interpretation of the wireless monitoring data is paramount when contemplating surgical intervention for those with gastroesophageal reflux disease. The aim of this study is to evaluate the incidence of false-positive interpretations of this wireless monitoring data secondary to premature transit of the Bravo capsule into the stomach and subsequently into the duodenum prior to the completion of the 48-h study period. We reviewed 100 consecutive Bravo pH studies at our University Esophageal Motility Center. There were 58 women and 42 men included in our evaluation. Premature transit of the Bravo capsule into the stomach and subsequently into the small bowel was defined by a prolonged gastric pH phase with either evidence of alkalinization and no further reflux episodes or loss of communication with the Bravo capsule prior to the end of the 48-h data collection period. Of the 100 patients reviewed, 11% manifested evidence of early passage of the Bravo capsule resulting in a misinterpretation of the data as abnormal acid exposure. The mean time of inaccurate data after transit of the Bravo capsule was 18 h and 42 min. The mean length of time that the capsule was retained in the stomach prior to duodenal passage was 4 h. If the aforementioned data were included in the final interpretation of the study, it yielded a mean DeMeester score of 44.25 with a mean total time of pH <4 of 14.7% per case. Exclusion of the prolonged gastric phase from the final interpretation of each case resulted in a statistically significant reduction in the mean total time the pH <4 (4.33 vs. 14.7%, p < 0.05) and the mean DeMeester score (12.81 vs. 44.25 p < 0.05). The mean time from the initiation of esophageal pH data to the passage of the Bravo capsule into the stomach was 15 h and 22 min. The observation mandates meticulous inspection of the pH tracing by the interpreting physician throughout the entirety of a 48-h study to identify premature transit of the capsule. Tracings that show prolonged acid exposure or loss of communication with the Bravo capsule should be screened for the capsule’s possible early dislodgement and premature advancement into the stomach.     

Adenosine-insensitive focal atrial tachycardia: evidence for de novo micro-re-entry in the human atrium.

OBJECTIVES: The purpose of this work was to describe the entity and mechanism of adenosine-insensitive focal atrial tachycardia (AT). BACKGROUND: The majority of regular focal ATs demonstrate properties consistent with triggered activity, including termination by adenosine. Less commonly, AT may be due to enhanced automaticity, which is transiently suppressed by adenosine. Small re-entrant circuits may also give rise to focal AT, but limited data exist regarding this entity as a de novo arrhythmia in the human atrium. METHODS: Eighty cases of focal AT were mapped in the electrophysiology laboratory and challenged with adenosine. Adenosine-sensitive and -insensitive groups were compared with regard to demographics, anatomical distribution, and electrogram characteristics at the tachycardia origin. RESULTS: In response to adenosine, termination occurred in 67 cases (84%), transient suppression in 5 (6%), 6 were insensitive (8%), and 2 exhibited nonspecific responses. Adenosine-insensitive AT arose near the pulmonary vein ostia (4) and from the right atrium (2), whereas adenosine-sensitive AT arose from a wide distribution in both atria. Electrograms at the site of origin for adenosine-insensitive AT were highly fractionated, with longer durations and lower amplitudes compared with AT that terminated or was transiently suppressed. The electrograms at the origin of adenosine-insensitive ATs comprised 22% to 69% of the tachycardia cycle length, compared with 4% to 21% for adenosine-sensitive ATs. In 3 adenosine-insensitive ATs, entrainment was demonstrated with post-pacing intervals equivalent to the tachycardia cycle length. CONCLUSIONS: The characteristics of adenosine-insensitive focal AT differ from adenosine-sensitive AT and are consistent with small re-entrant circuits. These data provide evidence that focal re-entry is a mechanism of AT and has an electropharmacologic profile that differs from AT due to automaticity and triggered activity.     

Inhibition of CYP2C9 by selective serotonin reuptake inhibitors in vitro: studies of phenytoin p-hydroxylation

Aims Inhibition of cytochrome P450 (CYP) activity by selective serotonin reuptake inhibitors (SSRIs) has frequently been reported with regard to pathways mediated by CYP2D6, CYP3A4/5, and CYP1A2. Little data exist on the capability of SSRIs to inhibit CYP2C9.
Methods We investigated the effect of SSRIs on p -hydroxylation of phenytoin (PPH), an established index reaction reflecting CYP2C9 activity, in an in vitro assay using liver tissue from six different human donors.
Results In control incubations (without inhibitor), 5-( p -hydroxy-phenyl)-5phenylhydantoin (HPPH) formation rates were: V _max 0.023  nmol min⁻¹  mg⁻¹; K _m 14.3  &mgr;m. Average inhibition constants ( K _i ) differed significantly among the SSRIs, with fluvoxamine having the lowest K _i (6  &mgr;m ) followed by R-fluoxetine (13  &mgr;m ), norfluoxetine (17  &mgr;m ), RS-fluoxetine (19  &mgr;m ), sertraline (33  &mgr;m ), paroxetine (35  &mgr;m ), S-fluoxetine (62  &mgr;m ), and desmethylsertraline (66  &mgr;m ). Thus, assuming comparable molar concentrations at the site of inhibition, fluvoxamine can be expected to have the highest probability of interfering with the metabolism of CYP2C9 substrates. S-fluoxetine is on average a 5 fold weaker CYP2C9 inhibitor than either R-fluoxetine or the racemic mixture.
Conclusions These findings are consistent with published case reports describing SSRI-related increments in plasma phenytoin levels. Because phenytoin has a narrow therapeutic index, plasma levels should be closely monitored when SSRIs are coadministered.     

Selection of peptides binding to the amyloid b-protein reveals potential inhibitors of amyloid formation.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular amyloid plaques, cerebrovascular amyloid deposits, intracellular neurofibrillary tangles, and neuronal loss. Amyloid deposits are composed of insoluble fibers of a 39-43 amino acid peptide named the amyloid beta-protein (A beta). Neuropathological and genetic studies provide strong evidence of a key role for A beta amyloidosis in the pathogenesis of AD. Therefore, an obvious pharmacological target for treatment of AD is the inhibition of amyloid growth and/or inhibition of amyloid function. We took an unbiased approach to generate new inhibitors of amyloid formation by screening a FliTrx combinatorial peptide library for A beta binding peptides and identified four groups of peptides with different A beta binding motifs. In addition, we designed and examined peptides mimicking the A beta binding domain of transthyretin (TTR). Our results showed that A beta binding peptides selected from FliTrx peptide library and from TTR-peptide analogs are capable of inhibiting A beta aggregation and A beta deposition in vitro. These properties demonstrate that binding of selected peptides to the amyloid beta-protein may provide potent therapeutic compounds for the treatment AD.     

Selective sensitization by nitric oxide of sympathetic baroreflex in rostral ventrolateral medulla of conscious rabbits

Nitric oxide (NO) deficiency in the rostral ventrolateral medulla (RVLM) has been implicated in impaired baroreflex control in hypertensive and heart failure animals. However, the role of local NO in normal baroreflex regulation remains unclear. This study aimed to examine the role of NO in tonic and baroreflex control of blood pressure (BP) in the RVLM of conscious rabbits. Microinjections of NO donors, S-nitroso-N-acetylpenicillamine and sodium nitroprusside (5 to 20 nmol), or NO itself (20 to 200 pmol) into the RVLM dose-dependently increased BP. Bilateral microinjections of an NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10 nmol), its inactive enantiomer D-NAME, or soluble guanylate cyclase (sGC) inhibitors, 1-H-[1,2,4]oxadiaolo[4,3-a]quinoxalin-1-one (ODQ, 250 pmol) and methylene blue (10 nmol), into the RVLM did not affect resting BP, heart rate, or renal sympathetic nerve activity (RSNA). However, L-NAME, methylene blue, and ODQ decreased RSNA baroreflex gain by 42% to 55%, whereas D-NAME did not affect this reflex. Co-microinjections of L-NAME and superoxide scavenger tempol (20 nmol) decreased RSNA baroreflex gain by 37+/-8%. Microinjections of a neuronal NOS (nNOS) inhibitor, 7-nitroindazole (500 pmol), into the RVLM decreased RSNA baroreflex gain by 42+/-12%, without altering resting BP, heart rate, or RSNA. Local administration of inducible NOS (iNOS) inhibitors, S-methylisothiourea (0.25 nmol) and aminoguanidine (0.25 and 2.5 nmol), affected neither resting nor baroreflex parameters. These results suggest that nNOS-derived NO facilitates sympathetic baroreflex transmission in the RVLM at least in part via a sGC-dependent, superoxide-independent mechanism. However, local nNOS and iNOS play little role in the tonic support of BP in conscious rabbits.     

K-ras mutations in sporadic colorectal tumors in Israel: unusual high frequency of codon 13 mutations and evidence for nonhomogeneous representation of mutation subtypes

Colorectal cancer is one of the most common malignancies in the western world, including Israel. An important step in progression includes induction of activating mutations in the protooncogene K-ras. This event is very frequent and is detected in about 40% of colorectal carcinomas. Previous studies of a variety of genetic disorders revealed unique gene mutation prevalence in Jewish populations, attributed both to differences in genetic background and to variability in environmental exposure. To determine the incidence and molecular subtypes of K-ras mutations in colorectal cancer in Israel, compared with other countries, DNA was isolated from a random collection of 105 colorectal carcinoma samples, and K-ras mutations were detected by an improved designed RFLP and direct sequencing. K-ras sporadic mutations in colorectal cancer in Israel are relatively frequent, with a higher fraction in codon 13 than reported thus far. Comparison with other countries shows a vast heterogeneity in terms of the relative abundance of the affected K-ras codon and in type and representation of specific mutations. The heterogeneous distribution found may be due to a variable genetic background and different environmental factors involved in the initiation and propagation of sporadic colorectal cancer.     

Alexithymia, depression and heart rate in candidates for cardiac surgery

Effects of psychological traits on heart rate (HR) and heart rate variability (HRV) were evaluated in patients awaiting cardiac surgery. Alexithymics demonstrated slowed HR, whereas high cognitive performance was associated with elevated HR in 2-3 days before surgery. Depression negatively correlated with HRV low frequency power. These data are consistent with previous findings of diverse moderate stress effects on HR regulation in cardiologic patients and healthy subjects in accordance to differences in psychological characteristics.     

Performance of the ablation index during pulmonary vein isolation: periprocedural data from a multicenter registry

Journal of Interventional Cardiac Electrophysiology - Our study aimed to assess the achievement of target ablation index (AI) values and their impact on first-pass pulmonary vein isolation (FPI) as...     

Dynamic Assessment of Pulmonary Artery Pulsatility Index Provides Incremental Risk Assessment for Early Right Ventricular Failure After Left Ventricular Assist Device

BackgroundThe pulmonary artery pulsatility index (PAPi) has been studied to predict right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation, but only as a single time point before LVAD implantation. Multiple clinical factors and therapies impact RV function in pre-LVAD patients. Thus, we hypothesized that serial PAPi measurements during cardiac intensive care unit (CICU) optimization before LVAD implantation would provide incremental risk stratification for early RVF after LVAD implantation.Methods and ResultsConsecutive patients who underwent sequential pulmonary artery catherization with cardiac intensive care optimization before durable LVAD implantation were included. Serial hemodynamics were reviewed retrospectively across the optimization period. The optimal PAPi was defined by the initial PAPi + the PAPi at optimized hemodynamics. RVF was defined as need for a right ventricular assist device or prolonged inotrope use (>14 days postoperatively). Patients with early RVF had significantly lower mean optimal PAPi (3.5 vs 7.5, P < .001) compared with those who did not develop RVF. After adjusting for established risk factors of early RVF after LVAD implantation, the optimal PAPi was independently and incrementally associated with early RVF after LVAD implantation (odds ratio 0.64, 95% confidence interval 0.532–0.765, P < .0001).ConclusionsOptimal PAPi achieved during medical optimization before LVAD implantation provides independent and incremental risk stratification for early RVF, likely identifying dynamic RV reserve.