Influence of naloxone on the effects of high frequency transcutaneous electrical nerve stimulation in angina pectoris induced by atrial pacing.

The influence of naloxone on the effects of high frequency transcutaneous electrical nerve stimulation in angina pectoris induced by atrial pacing was studied in 11 patients with severe coronary artery disease. The patients were catheterised and treated with transcutaneous electrical nerve stimulation on two occasions, double blind and in random order, with a single intravenous dose of saline or with a single intravenous dose of 50 mg naloxone. Treatment with transcutaneous electrical nerve stimulation increased tolerance to pacing and significantly improved lactate metabolism with placebo and with naloxone. The positive effects of transcutaneous electrical nerve stimulation were thus reproducible and not reversed by single intravenous doses of naloxone. The results indicate that the effects of transcutaneous electrical nerve stimulation on the heart are not mediated by beta endorphin but they do not exclude activation of more short-acting opioids such as delta or kappa receptor agonists (met-enkephalin or dynorphin or both) because naloxone has a low affinity for these receptors. Non-opioid mechanisms may also be important.     

Systemic Absorption and Block after Epidural Injection of Ropivacaine in Healthy Volunteers

Background: For local anesthetics, the process of removal from the site of administration influences the duration of anesthesia and the risk for systemic toxicity to develop. The systemic absorption of epidural ropivacaine and the time profile of sensory and motor block were studied in healthy volunteers.

Methods: Nine persons simultaneously received 150 mg ropivacaine hydrochloride (7.5 mg/ml) epidurally and 40 mg deuterium-labeled (sup 2 H sub 3)ropivacaine hydrochloride (0.25 mg/ml) intravenously. Peripheral arterial and venous plasma samples were collected, and assessments of sensory and motor block were made.

Results: The arterial plasma concentrations increased faster than the venous concentrations, with 50% higher maximum concentrations after both intravenous and epidural administration. The absorption was biphasic. A correlation was seen between the duration of sensory block and the slower absorption half-life; that is, the longer the half-life, the longer the duration. The extent of spread varied among the volunteers, with the median upper block level not exceeding T12. The motor block (Bromage score 1) was of slower onset (median, 0.4 h) and of shorter duration (median, 4.1 h) than the sensory block (onset, 0.2 h; duration, 6.5 h at L2 medians).     

Endogenous kynurenic acid disrupts prepulse inhibition.

BACKGROUND: Recent studies show that endogenous levels of kynurenic acid (KYNA) are increased in the cerebrospinal fluid of schizophrenic patients. Prepulse inhibition (PPI) of the acoustic startle reflex is an operational measure of sensorimotor gating that is reduced in neuropsychiatric disorders, such as schizophrenia. Previous studies show that administration of N-methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine or MK-801, leads to deficits in sensorimotor gating that mimic those observed in schizophrenic patients. METHODS: The present study examined the effects of the endogenous NMDA receptor antagonist KYNA on startle and PPI in rats. Elevation of endogenous brain levels of KYNA was achieved through intraperitoneal (IP) administration of kynurenine (100 mg/kg), the precursor of KYNA, or by intravenous administration of PNU 156561A (10 mg/kg). RESULTS: A fourfold increase in brain KYNA levels, as induced by kynurenine or PNU 156561A, significantly reduced PPI. There were no differences in startle magnitudes between control rats and drug-treated rats. The disruption of PPI was restored by administration of the antipsychotic drugs haloperidol (.2 mg/kg, IP) or clozapine (7.5 mg/kg, IP). CONCLUSIONS: The present results suggest that brain KYNA serves as an endogenous modulator of PPI and are consistent with the hypothesis that KYNA contributes to the pathophysiology of schizophrenia.     

Coagulation and complement activation

The purpose of this investigation was to assess the effect of heparin coating of a new stent construction (Stent Graft, Jomed Implantate GmbH, Germany) on platelet and coagulation activity. METHODS: Stent grafts with an ePTFE membrane interfoliated between two stents were deployed in tubings to form Chandler loops. Fresh human blood with a low concentration of heparin was rotated for 1 h, then collected and used for measurements of platelet number, thrombin-antithrombin complex (TAT), CD11b, C3a and C5b-9. There were five study groups: Group 1, conventional unmodified stents (n = 8); Group 2, untreated stent grafts (n = 8); Group 3, heparin-coated stents and untreated membrane (n = 7); Group 4, heparin-coated stents and membrane (n = 8); Group 5, heparin-coated PVC tubings with no stents (n = 8). RESULTS: There was a significant drop in platelet count, increase in TAT-values and CD11b expression in Groups 1-3 but not in Group 4 compared to Group 5. Examination by scanning electron microscopy revealed extensive activation on non-modified stents but almost no deposition of thrombotic material on heparin-modified stent grafts. CONCLUSIONS: With unmodified stents and membrane there were signs of significant activation of platelets and coagulation. In contrast, the heparin-coated stent graft induced much less alterations, indicating improved blood compatibility.     

Genetic analysis of the RNASEL gene in hereditary, familial, and sporadic prostate cancer.

PURPOSE: The RNASEL gene has been proposed as a candidate gene for the HPC1 locus through a positional cloning and candidate gene approach. Cosegregation between the truncating mutation E265X and disease in a hereditary prostate cancer (HPC) family and association between prostate cancer risk and the common missense variant R462Q has been reported. To additionally evaluate the possible role of RNASEL in susceptibility to prostate cancer risk, we performed a comprehensive genetic analysis of sequence variants in RNASEL in the Swedish population. EXPERIMENTAL DESIGN: Using 1624 prostate cancer cases and 801 unaffected controls, the truncating mutation E265X and five common sequence variants, including the two missense mutations R462Q and D541E, were evaluated for association between genotypes/haplotypes and prostate cancer risk. RESULTS: The prevalence of E265X carriers among unaffected controls and prostate cancer patients was almost identical (1.9 and 1.8% in controls and cases, respectively), and evidence for segregation of E265X with disease was not observed within any HPC family. Overall, the analyses of common sequence variants provided limited evidence for association with prostate cancer risk. We found a marginally significant inverse association between the missense mutation D541E and sporadic prostate cancer risk (odds ratio, 0.77; 95% confidence interval, 0.59-1.00) and reduced risk of prostate cancer in carriers of two different haplotypes being completely discordant. CONCLUSIONS: Considering the high quality in genotyping and the size of this study, these results provide solid evidence against a major role of RNASEL in prostate cancer etiology in Sweden.     

A case of arrhythmogenic right ventricular dysplasia with ventricular fibrillation

A case of repeated attacks of ventricular fibrillation is described. The patient suffered from an arrhythmogenic right ventricular dysplasia (ARVD) documented by right and left ventriculograms and myocardial biopsies obtained during surgical treatment of the arrhythmia. The histological changes were interpreted as being signs of fresh myocardial damage of unknown origin in addition to a replacement of the normal myocardium by adipose and fibrotic tissue. The repeated attacks of ventricular fibrillation in this patient contrast to the arrhythmia spectrum noted in the available literature on ARVD, mostly stable chronic ventricular tachycardias.     

Hereditary uveal melanoma: A report of a germline mutation in BAP1

Melanoma of the eye is a rare and distinct subtype of melanoma, which only rarely are familial. However, cases of uveal melanoma (UM) have been found in families with mixed cancer syndromes. Here, we describe a comprehensive search for inherited genetic variation in a family with multiple cases of UM but no aggregation of other cancer diagnoses. The proband is a woman diagnosed with UM at 16 years who within 6 months developed liver metastases. We also identified two older paternal relatives of the proband who had died from UM. We performed exome sequencing of germline DNA from members of the affected family. Exome‐wide analysis identified a novel loss‐of‐function mutation in the BAP1 gene, previously suggested as a tumor suppressor. The mutation segregated with the UM phenotype in this family, and we detected a loss of the wild‐type allele in the UM tumor of the proband, strongly supporting a causative association with UM. Screening of BAP1 germline mutations in families predisposed for UM may be used to identify individuals at increased risk of disease. Such individuals may then be enrolled in preventive programs and regular screenings to facilitate early detection and thereby improve prognosis. © 2013 Wiley Periodicals, Inc.     

Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes.

OBJECTIVES: In a substudy of DISPERSE (Dose confIrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in non-ST-segment Elevation myocardial infarction)-2, we compared the antiplatelet effects of AZD6140 and clopidogrel and assessed the effects of AZD6140 in clopidogrel-pretreated patients. BACKGROUND: Clopidogrel, in combination with aspirin, reduces cardiovascular events in patients with acute coronary syndromes (ACS). However, patients with poor inhibition of platelet aggregation with clopidogrel may be less well protected. AZD6140 is a reversible oral P2Y(12) receptor antagonist that has been studied in ACS patients in comparison with clopidogrel (DISPERSE-2 study). METHODS: Patients were randomized to receive either AZD6140 90 mg twice a day, AZD6140 180 mg twice a day, or clopidogrel 75 mg once a day for up to 12 weeks in a double-blind, double-dummy design. One-half the patients allocated AZD6140 received a 270-mg loading dose. Patients randomized to receive clopidogrel were given a 300-mg loading dose unless they had already been treated with clopidogrel. Adenosine diphosphate-induced platelet aggregation was assessed by optical aggregometry on day 1 and at 4-week intervals. RESULTS: AZD6140 inhibited platelet aggregation in a dose-dependent fashion and both doses achieved greater levels of inhibition than clopidogrel (e.g., 4 weeks, 4-h postdose [mean (+/-SD)]: clopidogrel 64% [+/-22%], AZD6140 90 mg 79% [+/-22%], AZD6140 180 mg 95% [+/-8%]. AZD6140 also produced further suppression of platelet aggregation in patients previously treated with clopidogrel. CONCLUSIONS: AZD6140 exhibited greater mean inhibition of platelet aggregation than a standard regimen of clopidogrel in ACS patients. In addition, AZD6140 further suppressed platelet aggregation in clopidogrel pretreated patients.     

Analysis of the abdominal musculo-aponeurotic anatomy in rectus diastasis: comparison of CT scanning and preoperative clinical assessment with direct measurement intraoperatively

Purpose

To evaluate and compare the consistency of agreement of two methods for measuring abdominal rectus diastasis (ARD), preoperative computed tomography (CT) scanning and preoperative clinical assessment were compared with direct measurement intraoperatively.

Methods

Fifty-five consecutive patients were retrieved from an ongoing prospective randomised trial comparing two operative techniques for the repair of ARD. All patients underwent a preoperative clinical assessment and CT scan, and the results were compared with intraoperative measurement of the ARD width. Agreement between methods was described with Bland–Altman plots (BA plots) and calculated using Lin’s Concordance Correlation Coefficient (CCC).

Results

The median width of the diastasis was 4.0 cm in the upper midline and 3.0 cm in the lower midline for the intraoperative measurement. BA plots showed that measurements on CT and intraoperatively are not in agreement in the lower midline, whereas the agreement was stronger between the clinical and the intraoperative method. The CCC was higher for clinical vs. intraoperative measurement (0.479) than for CT vs. intraoperative measurement (?0.002) in the lower midline, although the agreement was over all low. CT scanning underestimated the width of the ARD when compared to 87 % of preoperative clinical assessments, and 83 % of intraoperative measurements. Preoperative clinical assessment overestimated ARD in 35 % when compared with intraoperative measurements.

Conclusion

Clinical assessment prior to surgery provides more accurate information than CT scanning in the assessment of ARD width. CT scanning underestimates ARD width when compared with intraoperative measurement.     

Inhibition of putrescine synthesis blocks development of the polychete Ophryotrocha labronica at gastrulation.

Development eggs of the polychete Ophryotrocha labronica were analyzed for polyamines during the first 6 days after fertilization. The spermine content dominated initially, but gradually decreased. It was surpassed by putrescine, which rapidly increased to a maximum on the 3rd day, i.e., at the inception of grastrulation. The spermidine content was low during the entire period. Treatment of eggs with the putrescine synthesis inhibitor alpha-methylornithine from the onset of development led to developmental arrest at gastrulation and to an abnormally low content of putrescine in the treated embryos. Methylglyoxal bis(guanylhydrazone), an inhibitor of spermine and spermidine synthesis, had no visible effect of development. Our observations strongly suggest that putrescine synthesis is indispensable in early embryonic development of Ophryotrocha.