Pharmacological preconditioning by diazoxide downregulates cardiac L-type Ca2+ channels

BACKGROUND AND PURPOSE

Pharmacological preconditioning (PPC) with mitochondrial ATP-sensitive K⁺ (mitoK_ATP) channel openers such as diazoxide, leads to cardioprotection against ischaemia. However, effects on Ca²⁺ homeostasis during PPC, particularly changes in Ca²⁺ channel activity, are poorly understood. We investigated the effects of PPC on cardiac L-type Ca²⁺ channels.

EXPERIMENTAL APPROACH

PPC was induced in isolated hearts and enzymatically dissociated cardiomyocytes from adult rats by preincubation with diazoxide. We measured reactive oxygen species (ROS) production and Ca²⁺ signals associated with action potentials using fluorescent probes, and L-type currents using a whole-cell patch-clamp technique. Levels of the α_1c subunit of L-type channels in the cellular membrane were measured by Western blot.

KEY RESULTS

PPC was accompanied by a 50% reduction in α_1c subunit levels, and by a reversible fall in L-type current amplitude and Ca²⁺ transients. These effects were prevented by the ROS scavenger N-acetyl-L-cysteine (NAC), or by the mitoK_ATP channel blocker 5-hydroxydecanoate (5-HD). PPC signficantly reduced infarct size, an effect blocked by NAC and 5-HD. Nifedipine also conferred protection against infarction when applied during the reperfusion period. Downregulation of the α_1c subunit and Ca²⁺ channel function were prevented in part by the protease inhibitor leupeptin.

CONCLUSIONS AND IMPLICATIONS

PPC downregulated the α_1c subunit, possibly through ROS. Downregulation involved increased degradation of the Ca²⁺ channel, which in turn reduced Ca²⁺ influx, which may attenuate Ca²⁺ overload during reperfusion.     

Transvaginal and transabdominal sonography: prospective comparison

Transvaginal (TV) and transabdominal (TA) sonography were compared in a prospective study. A total of 230 examinations (126 pelvic, 104 pregnancy) were performed on 215 patients, ranging in age from 14 to 80 years. The improved anatomic detail on TV scans yielded new information in 138 (60%) examinations and better visualization of pelvic structures in 51 (22%) examinations. There was no important difference in diagnostic information provided by the two imaging modalities in 36 (16%) cases, and TV images were worse in five (2%). The clinical diagnosis was altered on the basis of TV sonographic findings in 54 (24%) cases and confirmed with certainty in 166 (72%). Diagnostic problems posed by TA scanning were not resolved by TV scanning in ten (4%) instances. Statistical analysis indicated that TV scanning was significantly better than TA scanning in the visualization of gestational sac contents (P less than .005), detection of fetal heart motion (P less than .001), and evaluation of the endometrial canal in the retroverted or retroflexed uterus (P less than .001). TV scanning was significantly better than TA scanning in visualization of the ovaries in patients with uterine leiomyomas (P less than .005) but not significantly better in peri- and postmenopausal patients (P greater than .05).     

Low-phase angle in body composition measurements correlates with prolonged hospital stay in head and neck cancer patients

Background: Bioelectrical impedance analysis (BIA) is a method for estimating body composition. Clinically the most important parameter is the phase angle (PA), which decreases with progressing malnutrition and is highly predictive for impaired survival and mortality.

Aim: To evaluate the association of low PA with the complication rate and length of hospital stay.

Material and methods: A cohort of 61 head and neck cancer (HNC) patients underwent BIA prior to surgical treatment. Information on patient and tumour characteristics, treatment, and surgical complications were gathered from hospital records and correlated with BIA results.

Results: The median PA was 4.5 (range, 2.7–6.5), and, in 67% of the patients, it was lower than reference values. Low PA was associated with longer hospital stay (p?=?.002) in the whole cohort and in the patient group with radical neck dissections it correlated with a higher surgical complication rate (p?=?.014), but not with Clavien–Dindo scoring for surgical complications.

Conclusions and significance: BIA is a feasible instrument for analysing body composition that reflects nutritional status in cancer patients. Our results show that HNC patients have a low PA at diagnosis. Low PA is associated with a long hospital stay and an increase in the complication rate. BIA can be of clinical value in preoperative risk evaluation.     

Spatial localization in visual impairment

PURPOSE: To investigate self-reported difficulties experienced by visually impaired subjects in real-world tasks requiring judgment of space and distance and to determine whether laboratory measures of spatial localization predict self-reported difficulty with spatial tasks better than traditional measures of visual function, such as visual acuity and contrast sensitivity. METHODS: Forty-two subjects with visual impairment participated. The Spatial Localization Questionnaire (SLQ) was developed to investigate self-reported spatial localization difficulties, and subjects answered the questionnaire as part of the study. Subjects also completed a variety of clinical vision tests (visual acuity, contrast sensitivity, stereo acuity, and reading speed) and laboratory vision tests (vernier acuity, bisection acuity, and visual direction). RESULTS: The SLQ was found to have good validity. Several significant correlations were found between the Rasch analysis ability scores for the questionnaire and the clinical and laboratory vision tests. Using stepwise regression analysis, we found that vernier acuity and contrast sensitivity accounted for 42% of the variance in the Rasch scores (P < 0.001). CONCLUSIONS: The findings indicate that certain subjects with visual impairment have difficulty with real-world spatial tasks, as indicated by the SLQ. Of note, these difficulties were better predicted by vernier acuity (a resolution test) and contrast sensitivity, rather than vernier or bisection bias, which measure localization.     

Abnormal in vitro proliferation and differentiation of T colony-forming cells in patients with lymphadenopathy syndrome

Patients with acquired immunodeficiency syndrome (AIDS) present impaired colony growth and in vitro differentiation capacity of peripheral blood and bone marrow T colony-forming cells (T-CFC). We show that peripheral blood, bone marrow, and lymph node T-CFC from patients with persistent lymphadenopathy syndrome (LAS), a syndrome that can precede AIDS, displayed similar abnormalities. Indeed, peripheral blood T-CFC generated a low number of colonies in seven out of 12 patients, and almost no colonies were obtained from bone marrow cells of all patients. The simultaneous study of T-CFC from peripheral blood and lymph node mononuclear cells seems to provide a reliable indicator for the risk of developing AIDS. The six patients who developed AIDS displayed extremely low numbers of peripheral blood T- CFC (13 +/- 17 colonies per 5 X 10(4) cells), and in two of them, no colonies could be obtained from lymph node T-CFC. The remaining patients who had not developed AIDS displayed a higher number of peripheral blood T-CFC (141 +/- 113 per 5 X 10(4) cells) and lymph node T-CFC, which, in addition, preserved their clonogenic capacity. In some patients, peripheral blood and lymph node, but not bone marrow, T-CFC were capable of generating colonies in the absence of added growth factors or mitogens, whereas in others, colony formation was obtained with purified interleukin 2 (IL 2) alone. Both spontaneous and IL 2- induced colony formation was abrogated by a monoclonal antibody against the IL 2 receptor. Taken together, these findings suggest that at least some T-CFC expressed IL 2 receptors. Colonies generated either in the presence or in the absence of added growth factors were composed of T4+, T6+, and T8+ cells, indicating impaired in vitro T-CFC differentiation. These findings indicate that a dramatic quantitative and qualitative impairment of the proliferation and differentiation of peripheral blood and lymph node T-CFC precedes the clinical evolution from LAS to AIDS.     

The diagnosis and treatment of cerebral mycotic aneurysms

Seventeen patients were treated for 28 documented cerebral mycotic aneurysms. Initial neurological symptoms were attributable to aneurysm rupture in only 7 patients, and in 3 of them symptoms did not suggest subarachnoid hemorrhage. Six patients presented with embolic infarction and 1 with meningitis; in 3 patients it was uncertain if aneurysm rupture occurred. Four patients had rupture of at least one aneurysm while receiving appropriate antibiotic treatment and another had rupture at the conclusion of therapy. Of 20 aneurysms followed angiographically or with computed tomography during medical treatment, 10 became smaller or disappeared and 10 remained unchanged or enlarged, 1 with fatal rupture. Eight ruptured aneurysms were surgically excised; 2 of the patients with ruptured aneurysms died and 2 had residual aphasia or cognitive impairment. All 4 patients whose only surgery was for an unruptured aneurysm made uneventful recoveries. Recognizing the retrospective and anecdotal nature of our data and the differing views of previous investigators, we recommend: (1) that careful neurological examination, computed tomography, and (unless contraindicated) lumbar puncture be performed on any patient with endocarditis; (2) that those with neurological abnormalities not attributable to systemic toxicity, including pleocytosis in the cerebrospinal fluid or apparent infarction on computed tomographic scans, undergo four-vessel cerebral angiography; (3) that single accessible mycotic aneurysms in medically stable patients be promptly excised, with individualization of multiple or proximal aneurysms; and (4) that repeat angiography be performed at the conclusion of antibiotic therapy in patients requiring long-term anticoagulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Percutaneous Intraductal Radiofrequency Ablation is a Safe Treatment for Malignant Biliary Obstruction: Feasibility and Early Results

Purpose

Previous clinical studies have shown the safety and efficacy of this novel radiofrequency ablation catheter when used for endoscopic palliative procedures. We report a retrospective study with the results of first in man percutaneous intraductal radiofrequency ablation in patients with malignant biliary obstruction.

Methods

Thirty-nine patients with inoperable malignant biliary obstruction were included. These patients underwent intraductal biliary radiofrequency ablation of their malignant biliary strictures following external biliary decompression with an internal-external biliary drainage. Following ablation, they had a metal stent inserted.

Results

Following this intervention, there were no 30-day mortality, hemorrhage, bile duct perforation, bile leak, or pancreatitis. Of the 39 patients, 28 are alive and 10 patients are dead with a median survival of 89.5 (range 14–260) days and median stent patency of 84.5 (range 14–260) days. One patient was lost to follow-up. All but one patient had their stent patent at the time of last follow-up or death. One patient with stent blockage at 42 days postprocedure underwent percutaneous transhepatic drain insertion and restenting. Among the patients who are alive (n = 28) the median stent patency was 92 (range 14–260) days, whereas the patients who died (n = 10) had a median stent patency of 62.5 (range 38–210) days.

Conclusions

In this group of patients, it appears that this new approach is feasible and safe. Efficacy remains to be proven in future, randomized, prospective studies.