Expression of pannexin isoforms in the systemic murine arterial network

Aims: Pannexins (Panx) form ATP release channels and it has been proposed that they play an important role in the regulation of vascular tone. However, distribution of Panx across the arterial vasculature is not documented. Methods: We tested antibodies against Panx1, Panx2 and Panx3 on human embryonic kidney cells (which do not endogenously express Panx proteins) transfected with plasmids encoding each Panx isoform and Panx1(-/-) mice. Each of the Panx antibodies was found to be specific and was tested on isolated arteries using immunocytochemistry. Results: We demonstrated that Panx1 is the primary isoform detected in the arterial network. In large arteries, Panx1 is primarily in endothelial cells, whereas in small arteries and arterioles it localizes primarily to the smooth muscle cells. Panx1 was the predominant isoform expressed in coronary arteries, except in arteries less than 100 μm where Panx3 became detectable. Only Panx3 was expressed in the juxtaglomerular apparatus and cortical arterioles. The pulmonary artery and alveoli had expression of all 3 Panx isoforms. No Panx isoforms were detected at the myoendothelial junctions. Conclusion: We conclude that the specific localized expression of Panx channels throughout the vasculature points towards an important role for these channels in regulating the release of ATP throughout the arterial network.     

The effects of difficulty and gain versus loss on vocal physiology and acoustics

To examine the basis of emotional changes to the voice, physiological and electroglottal measures were combined with acoustic speech analysis of 30 men performing a computer task in which they lost or gained points under two levels of difficulty. Predictions of the main effects of difficulty and reward on the voice were not borne out by the data. Instead, vocal changes depended largely on interactions between gain versus loss and difficulty. The rate at which the vocal folds open and close (fundamental frequency; fo) was higher for loss than for gain when difficulty was high, but not when difficulty was low. Electroglottal measures revealed that fo changes corresponded to shorter glottal open times for the loss conditions. Longer closed and shorter open phases were consistent with raised laryngeal tension in difficult loss conditions. Similarly, skin conductance indicated higher sympathetic arousal in loss than gain conditions, particularly when difficulty was high. The results provide evidence of the physiological basis of affective vocal responses, confirming the utility of measuring physiology and voice in the study of emotion.     

Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist

Histone deacetylase inhibitors (HDACi) and agents such as recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic anti-TRAIL receptor (TRAIL-R) antibodies are anticancer agents that have shown promise in preclinical settings and in early phase clinical trials as monotherapies. Although HDACi and activators of the TRAIL pathway have different molecular targets and mechanisms of action, they share the ability to induce tumor cell-selective apoptosis. The ability of HDACi to induce expression of TRAIL-R death receptors 4 and 5 (DR4/DR5), and induce tumor cell death via the intrinsic apoptotic pathway provides a molecular rationale to combine these agents with activators of the TRAIL pathway that activate the alternative (death receptor) apoptotic pathway. Herein, we demonstrate that the HDACi vorinostat synergizes with the mouse DR5-specific monoclonal antibody MD5-1 to induce rapid and robust tumor cell apoptosis in vitro and in vivo. Importantly, using a preclinical mouse breast cancer model, we show that the combination of vorinostat and MD5-1 is safe and induces regression of established tumors, whereas single agent treatment had little or no effect. Functional analyses revealed that rather than mediating enhanced tumor cell apoptosis via the simultaneous activation of the intrinsic and extrinsic apoptotic pathways, vorinostat augmented MD5-1-induced apoptosis concomitant with down-regulation of the intracellular apoptosis inhibitor cellular-FLIP (c-FLIP). These data demonstrate that combination therapies involving HDACi and activators of the TRAIL pathway can be efficacious for the treatment of cancer in experimental mouse models.     

Intestinal obstruction promotes gut translocation of bacteria

PURPOSE: Translocation of enteric organisms has been implicated as a possible source of sepsis in susceptible patients. Animal studies have suggested that intestinal obstruction promotes bacterial translocation from the gut lumen. The aim of this study was to study the prevalence of bacterial translocation in patients with and without intestinal obstruction. METHODS: Serosal scrapings, mesenteric lymph nodes, and peripheral blood cultures were obtained from 254 patients. Scrapings and nodes were homogenized and incubated aerobically and anaerobically. Full-thickness biopsies underwent villous height analysis. The clinical course was followed for at least six weeks. RESULTS: Bacterial translocation to mesenteric nodes occurred more frequently in patients with large bowel obstruction than in patients without obstruction (14 of 36 patients vs.16 of 218 patients;P<0.001). Both aerobic and anaerobic bacteria were found to translocate. The more distal the obstruction, the more likely anaerobic bacteria were to be identified. Translocation of bacteria predisposed to postoperative septic complications (P<0.05). Villous height was not related to bacterial translocation. CONCLUSIONS: Gut translocation of bacteria is more common in patients with intestinal obstruction, and its association with septic complications appears to be of clinical significance.Supported by the Yorkshire Regional Health Authority Research Trust, Harrogate, United Kingdom.Read at the meeting of The American Society of Colon and Rectal Surgeons, Orlando, Florida, May 8 to 13, 1994.     

The value of prognostic indices for pneumonia

One of the most important decisions in the management of community-acquired pneumonia is deciding the care site, which affects morbidity, mortality, and costs. Clinical judgment alone is difficult and imprecise. The Pneumonia Severity Index score and the CURB-65 (confusion, urea nitrogen, respiratory rate, blood pressure, 65 years of age and older) score are validated prognostic indices to predict mortality, and they can identify low-risk patients who may be eligible for outpatient management. However, limitations of the scoring systems preclude their isolated use, and they can only be recommended as an aid to guide hospital admission decisions. The Pneumonia Severity Index score is slightly better at identifying the lowest risk patients, whereas CURB-65 is much simpler to use. As an adjunct to clinical judgment, we consider CURB-65 to be the most useful prognostic index for identifying low-risk patients.     

Undocumented patient information: an impediment to quality of care

PURPOSE: Poor documentation in medical records might reduce the quality of care and undermine analyses based on retrospective chart reviews. We assessed the documentation of cardiac risk factors and cardiac history in the records of patients hospitalized with myocardial infarction or heart failure. METHODS: We performed a retrospective cohort study involving direct chart audit of all consecutive hospitalizations for myocardial infarction (n = 2,109) or heart failure (n = 3,392) in Nova Scotia, Canada, from October 15, 1997, to October 14, 1998. The main outcome measures were the documentation rates for prespecified clinical items, including cardiac risk factors and history of myocardial infarction or heart failure, which were recognized as indicators of the quality of care for the conditions under study. RESULTS: Information was not documented in a high proportion of cases, ranging from 9% (smoking) to 58% (previous history of heart failure) in charts from patients hospitalized for myocardial infarction, and from 19% (smoking) to 69% (hyperlipidemia) in charts from heart failure hospitalizations. Lack of documentation was more common in women and the elderly. CONCLUSION: Documentation of important clinical information is poor even in the hospital charts of patients with severe conditions. This quality-of-care issue has implications for health services and outcomes research, including the development of report cards.     

Global and regional left ventricular response to bicycle exercise in coronary artery disease. Assessment by quantitative radionuclide angiocardiography.

The left ventricular response to bicycle exercise was evaluated in 60 patients with coronary artery disease and in 13 normal control subjects. Left ventricular ejection fraction, mean normalized ejection rate and regional wall motion were determined using first-pass radionuclide angiocardiograms obtained at rest and again during peak graded bicycle exercise. All normal subjects demonstrated improved left ventricular function with exercise. Left ventricular ejection fraction increased significantly from 67 ± 3 per cent (mean ± SE) at rest to 82 ± 4 per cent with exercise (p < 0.001). Similarly, the left ventricular ejection rate increased significantly from 3.47 ± 0.31 sec^?1 to 6.53 ± 0.42 sec^?1(p < 0.001). In contrast, in 44 of 60 patients with coronary artery disease, the ejection fraction or ejection rate either decreased or remained the same with exercise. New or exaggerated regional wall motion abnormalities were detected in 28 of 60 patients with coronary artery disease. Over-all, global or regional evidence of compromised left ventricular reserve was found in 48 of 60 patients with coronary artery disease.The major determinant of an abnormal left ventricular response to exercise was the presence or absence of electrocardiographic evidence of myocardial ischemia. Left ventricular ejection fraction decreased or remained the same with exercise in all patients with coronary artery disease and electrocardiographic ischemia. New regional wall motion abnormalities were detected in 20 of these patients. In this group, the left ventricular ejection fraction decreased from 66 ± 2 per cent at rest to 58 ± 2 per cent with exercise (p < 0.001), whereas the ejection rate was unchanged by exercise (rest 3.33 ± 0.21 sec^?1; exercise 3.34 ± 0.22 sec^?1, p > 0.05). Of the 30 patients with coronary artery disease who exercised to symptom-limiting fatigue without electrocardiographic ischemia, 18 demonstrated compromised left ventricular reserve with exercise. Twelve of the remaining patients with coronary artery disease had normal left ventricular reserve, in eight of whom ventricular function was completely normal both at rest and during exercise. In this group exercised to fatigue, the left ventricular ejection fraction increased from 53 ± 4 per cent at rest to 58 ± 2 per cent with exercise (p < 0.001). The ejection rate also increased from 2.48 ± 0.24 sec^?1 to 3.67 ± 0.39 sec^?1 (p < 0.001). The direction and magnitude of the left ventricular responses to exercise were not affected by long-term oral propranolol administration in 22 patients. Based upon either abnormal exercise left ventricular reserve or abnormal global and regional left ventricular function at rest, the over-all sensitivity of this radionuclide technic for the detection of coronary artery disease was 87 per cent (52 of 60 patients). These data demonstrate that exercise ventricular performance studies provide important physiologic insights into left ventricular functional reserve as well as a sensitive noninvasive approach for the detection of coronary artery disease.