Role of hemodynamics in initiation/growth of intracranial aneurysms

Background

Intracranial aneurysm (IA) is a disease of the vascular wall resulting in abnormal enlargement of the vessel lumen. It is a common pathology with a prevalence of 2%‐3% in the adult population. IAs are mostly small, quiescent and asymptomatic; yet, upon rupture, severe brain damage or even death is frequently encountered. In addition to clinical factors, hemodynamic forces, mainly wall shear stress (WSS), have been associated with the initiation of IAs and possibly with their risk of rupture. However, the mechanism by which WSS contributes to aneurysm growth and rupture is not completely understood.

Design

PubMed and Ovid MEDLINE databases were searched. In addition, key review articles were screened for relevant original publications.

Results

Current knowledge about the relation between WSS and IA has been obtained from both computational fluid dynamic studies in patients and experimental models of IA formation and growth. It is increasingly recognized that a high wall shear stress (gradient) participates to IA formation and that both low and high WSS can drive IA growth. Primary cilia (PC) play an important role as mechanosensors as patients with polycystic kidney disease, which is characterized by the absence or dysfunction of PC, have increased risk to develop IAs as well as increased risk of rupture.

Conclusion

Wall shear stress is a key player in IA initiation and progression. It is involved in vascular wall remodelling and inflammation, processes underlying aneurysm pathophysiology.     

Canadian Consensus Conference on the management of gastroesophageal reflux disease in adults - update 2004.

BACKGROUND: Gastroesophageal reflux disease (GERD) is the most prevalent acid-related disorder in Canada and is associated with significant impairment of health-related quality of life. Since the last Canadian Consensus Conference in 1996, GERD management has evolved substantially. OBJECTIVE: To develop up-to-date evidence-based recommendations relevant to the needs of Canadian health care providers for the management of the esophageal manifestations of GERD. CONSENSUS PROCESS: A multidisciplinary group of 23 voting participants developed recommendation statements using a Delphi approach; after presentation of relevant data at the meeting, the quality of the evidence, strength of recommendation and level of consensus were graded by participants according to accepted principles. OUTCOMES: GERD applies to individuals who reflux gastric contents into the esophagus causing symptoms sufficient to reduce quality of life, injury or both; endoscopy-negative reflux disease applies to individuals who have GERD and a normal endoscopy. Uninvestigated heartburn-dominant dyspepsia - characterised by heartburn or acid regurgitation - includes erosive esophagitis or endoscopy-negative reflux disease, and may be treated empirically as GERD without further investigation provided there are no alarm features. Lifestyle modifications are ineffective for frequent or severe GERD symptoms; over-the-counter antacids or histamine H2-receptor antagonists are effective for some patients with mild or infrequent GERD symptoms. Proton pump inhibitors are more effective for healing and symptom relief than histamine H2-receptor antagonists; their efficacy is proportional to their ability to reduce intragastric acidity. Response to initial therapy - a once-daily proton pump inhibitor unless symptoms are mild and infrequent (fewer than three times per week) - should be assessed at four to eight weeks. Maintenance medical therapy should be at the lowest dose and frequency necessary to maintain symptom relief; antireflux surgery is an alternative for a small proportion of selected patients. Routine testing for Helicobacter pylori infection is unnecessary before starting GERD therapy. GERD is associated with Barrett's epithelium and esophageal adenocarcinoma but the risk of malignancy is very low. Endoscopic screening for Barrett's epithelium may be considered in adults with GERD symptoms for more than 10 years; Barrett's epithelium and low-grade dysplasia generally warrant surveillance; endoscopic or surgical management should be considered for confirmed high-grade dysplasia or malignancy. CONCLUSION: Prospective studies are needed to investigate clinically relevant risk factors for the development of GERD and its complications; GERD progression, on and off therapy; optimal management strategies for typical GERD symptoms in primary care patients; and optimal management strategies for atypical GERD symptoms, Barrett's epithelium and esophageal adenocarcinoma.     

Pharmacology of phosphodiesterase 5 inhibitors

The phosphodiesterase enzymes, of at least 11 types, are ubiquitous throughout the body, and perform a variety of functions. Phosphodiesterase type 5 (PDE5) is the predominant enzyme in the corpus cavernosum, and plays a crucial role in penile erection. Inhibitors of PDE5 are the most effective oral agents in the treatment of erectile dysfunction. Sildenafil, tadalafil, and vardenafil are all potent inhibitors of PDE5 and show the same mechanism of action, although they have some pharmacological differences that may translate into varying clinical effects.     

Newer concepts of cancer of the colon and rectum: Clinical evaluation of a radioimmunoassay for CEA

Conclusions Using basically the same reagents and methodology, we have tried to duplicate the optimistic results of Goldet al. Of 578 samples submitted, 393 met the criteria for the study; results for these 393 are presented. Our results indicate that CEA can be detected not only in a smaller proportion of gastrointestinal malignancies than that found by Gold and associates, but also in a similar proportion of inflammatory bowel diseases. Furthermore, we found a significant number of positive in nongastrointestinal malignancies, as well as chronic inflammatory diseases and collagenoses. Therefore, we feel that the assay, in its present form, has limited value as a diagnostic tool in the detection of gastrointestinal malignancies. Better purification procedures, less sensitive methods of detection, or an entirely new approach may produce results of more clinical value than those we have obtained. Symposium presented at the meeting of the American Proctologic Society Las Vegas, Nevada, May 10 to 13, 1971. Presented in part at The Southern Medical Association Meeting, Dallas, Texas, November 16, 1970. Supported in part by grants from the American Cancer Society, Ohio Division, The Randall Foundation, and a donation from Mr. F. Ball.     

beta-Arrestin2, interacting with phosphodiesterase 4, regulates synaptic release probability and presynaptic inhibition by opioids

Most mu-opioid receptor agonists recruit beta-arrestin2, with some exceptions such as morphine. Surprisingly, however, the acute analgesic effect of morphine is enhanced in the absence of beta-arrestin2. To resolve this paradox, we examined the effects of morphine and fentanyl in acute brain slices of the locus coeruleus and the periaqueductal gray from beta-arrestin2 knockout mice. We report that, in these mice, presynaptic inhibition of evoked inhibitory postsynaptic currents was enhanced, whereas postsynaptic G protein-coupled K(+) (Kir3/GIRK) currents were unaffected. The frequency, but not amplitude, of miniature inhibitory postsynaptic currents was increased in beta-arrestin2 knockout mice, indicating a higher release probability compared to WT mice. The increased release probability resulted from increased cAMP levels because of impaired phosphodiesterase 4 function and conferred an enhanced efficacy of morphine to inhibit GABA release. Thus, beta-arrestin2 attenuates presynaptic inhibition by opioids independent of mu-opioid receptor-driven recruitment, which may make beta-arrestin2 a promising target for regulating analgesia.     

Permanent Cardiac Pacing in the Elderly Patient: Is Selection of the Pacing Mode Important?

Most pacemaker recipients are elderly, and advanced age does not constitute a contraindication to the implantation of a permanent pacemaker. However, pacing in the older patient should no longer be regarded simply as a way to prevent Stokes-Adams attacks or life-threatening bradyarrhythmia. A VVI pacemaker for everyone is now inappropriate, especially in active and otherwise healthy older patients. Selection of the optimal devise or pacing mode in older patients requires an understanding of how aging affects the cardiovascular system (left ventricular diastolic dysfunction) and the natural history of disease, especially sick sinus syndrome after pacemaker implantation. Many retrospective and nonrandomized studies focusing mostly on the sick sinus syndrome have indicated that atrial-based pacing improves the quality and duration of life when compared to single lead ventricle pacing. The lower incidence of chronic atrial fibrillation in patients with atrial-based pacemakers compared to VVI devices is of great importance in the elderly, in whom this arrhythmia is associated with greater morbidity and mortality than in younger individuals. The decreased mortality associated with atrial-based pacing compared to single lead ventricular pacing seems to favor patients older than 70 years. There is now a growing realization that implantation of dual chamber pacemakers in the elderly is cost-effective on a long-term basis by avoiding or reducing the complications associated with single lead ventricular pacing, thereby reducing the need for repeated hospitalizations and medical care.     

Report on a novel emerging class of highly potent benzimidazole NPS opioids: Chemical and in vitro functional characterization of isotonitazene

This paper reports on the identification and full chemical characterization of isotonitazene (N,N‐diethyl‐2‐[5‐nitro‐2‐({4‐[(propan‐2‐yl)oxy]phenyl}methyl)‐1H‐benzimidazol‐1‐yl]ethan‐1‐amine), a potent NPS opioid and the first member of the benzimidazole class of compounds to be available on online markets. Interestingly, this compound was sold under the name etonitazene, a structural analog. Identification of isotonitazene was performed by gas chromatography mass spectrometry (GC–MS) and liquid chromatography time‐of‐flight mass spectrometry (LC‐QTOF‐MS), the latter identifying an exact‐mass m/z value of 411.2398. All chromatographic data indicated the presence of a single, highly pure compound. Confirmation of the specific benzimidazole regio‐isomer was performed using ¹H and ¹³C NMR spectroscopy, after which the chemical characterization was finalized by recording Fourier‐transform (FT‐IR) spectra. A live cell‐based reporter assay to assess the in vitro biological activity at the μ‐opioid receptor (MOR) revealed that isotonitazene has a high potency (EC₅₀ of 11.1 nM) and efficacy (E_max 180% of that of hydromorphone), thus confirming that this substance is a strong opioid. Isotonitazene has not been previously detected, either in powder form, or in biological fluids. The high potency and efficacy of isotonitazene, combined with the fact that this compound was being sold undiluted, represents an imminent danger to anyone aiming to use this powder.