IgE antithyroid antibodies in patients with Hashimoto's disease and chronic urticaria.

Although chronic urticaria may be associated with the presence of serum anti-thyroid antibodies, it is not known whether these antibodies play a causal role in the urticaria. We therefore sought to determine whether the anti-thyroid antibodies seen in patients with urticaria were of the IgE class. Using commercial ELISA kits for measuring serum IgG anti-thyroglobulin and anti-thyroid peroxidase antibodies, we modified the procedure to detect IgE antibodies. We examined sera from 20 patients with urticaria who had IgG anti-thyroid antibodies and from 12 patients with IgG antithyroid antibodies who did not have urticaria. Only 2 of 20 patients with urticaria and IgG anti-thyroid antibodies had detectable IgE anti-thyroid antibodies: 1 patient had anti-thyroid peroxidase IgE antibody and 1 patient had anti-thyroglobulin IgE. IgE anti-thyroid antibodies do not appear to play a causal role in urticaria in the majority of patients.     

Hepatobiliary transporters and drug-induced cholestasis

Drug-induced liver injury is an important clinical problem with significant morbidity and mortality. Whereas for most hepatocellular forms of drug-induced hepatic injury the underlying pathophysiological mechanism is poorly understood, there is increasing evidence that cholestatic forms of drug-induced liver damage result from a drug- or metabolite-mediated inhibition of hepatobiliary transporter systems. In addition to their key role in determining hepatic drug exposure and clearance, the coordinated action of these transport systems is essential for bile formation and the biliary secretion of cholephilic compounds and xenobiotics. Any drug-mediated functional disturbance of these processes can lead to an intracellular accumulation of potentially harmful bile constituents and result in the development of cholestatic liver cell damage. In addition to direct drug-mediated inhibition of hepatocellular transport, function of these transporters can be altered by pre-existing hepatic disease and genetic factors, which contribute to the development of drug-induced cholestasis in susceptible individuals. This review summarizes current knowledge about the function of hepatobiliary uptake and efflux systems and discusses factors that might predispose to drug-induced cholestasis.     

Coronary collateral perfusion in patients with coronary artery disease: effect of metoprolol.

BACKGROUND: The use of ultrathin Doppler angioplasty guidewires has made it possible to measure collateral flow quantitatively. Pharmacologic interventions have been shown to influence collateral flow and, thus, to affect myocardial ischaemia. METHODS: Twenty-five patients with coronary artery disease undergoing PTCA were included in the present analysis. Coronary flow velocities were measured in the ipsilateral (n = 25) and contralateral (n = 6; two Doppler wires) vessels during PTCA with and without i.v. adenosine (140 microg/kg.min) before and 3 min after 5 mg metoprolol i.v., respectively. The ipsilateral Doppler wire was positioned distal to the stenosis, whereas the distal end of the contralateral wire was in an angiographically normal vessel. The flow signals of the ipsilateral wire were used to calculate the collateral flow index (CFI). CFI was defined as the ratio of flow velocity during balloon inflation divided by resting flow. RESULTS: Heart rate and mean aortic pressure decreased slightly (ns) after i.v. metoprolol. The collateral flow index was 0.25+/-0.12 (one fourth of the resting coronary flow) during the first PTCA and 0.27+/-0.14 (ns versus first PTCA) during the second PTCA, but decreased with metoprolol to 0.16+/-0.08 (p<0.0001 vs. baseline) during the third PTCA. CONCLUSIONS: Coronary collateral flow increased slightly but not significantly during maximal vasodilatation with adenosine but decreased in 23 of 25 patients after i.v. metoprolol. Thus, there is a reduction in coronary collateral flow with metoprolol, probably due to an increase in coronary collateral resistance or a reduction in oxygen demand.     

Evolving potassium channels by means of yeast selection reveals structural elements important for selectivity

Potassium channels are widely distributed. To serve their physiological functions, such as neuronal signaling, control of insulin release, and regulation of heart rate and blood flow, it is essential that K+ channels allow K+ but not the smaller and more abundant Na+ ions to go through. The narrowest part of the channel pore, the selectivity filter formed by backbone carbonyls of the GYG-containing K+ channel signature sequence, approximates the hydration shell of K+ ions. However, the K+ channel signature sequence is not sufficient for K+ selectivity. To identify structural elements important for K+ selectivity, we randomly mutagenized the G protein-coupled inwardly rectifying potassium channel 3.2 (GIRK2) bearing the S177W mutation on the second transmembrane segment. This mutation confers constitutive channel activity but abolishes K+ selectivity and hence the channel's ability to complement the K+ transport deficiency of Deltatrk1Deltatrk2 mutant yeast. S177W-containing GIRK2 mutants that support yeast growth in low-K+ medium contain multiple suppressors, each partially restoring K+ selectivity to S177W-containing double mutants. These suppressors include mutations in the first transmembrane segment and the pore helix, likely exerting long-range actions to restore K+ selectivity, as well as a mutation of a second transmembrane segment residue facing the cytoplasmic half of the pore, below the selectivity filter. Some of these suppressors also affected channel gating (channel open time and opening frequency determined in single-channel analyses), revealing intriguing interplay between ion permeation and channel gating.     

Comparison of epicardial potential maps derived from the 12-lead electrocardiograms with scintigraphic images during controlled myocardial ischemia

Our aim was to cross-validate electrocardiographic (ECG) and scintigraphic imaging of acute myocardial ischemia. The former method was based on inverse calculation of heart-surface potentials from the body-surface ECGs, and the latter, on a single photon emission computed tomography (SPECT). A boundary-element torso model with 352 body-surface and 202 heart-surface nodes was used to perform the ECG inverse solution. Potentials at 352 body-surface nodes were calculated from those acquired at 12-lead ECG measurement sites using regression coefficients developed from a design set (n = 892) of body-surface potential mapping (BSPM) data. The test set (n = 18) consisted of BSPM data from patients who underwent a balloon-inflation angioplasty of either the left anterior descending coronary artery (LAD) (n = 7), left circumflex coronary artery (LCx) (n = 2), or the right coronary artery (RCA) (n = 9). Body-surface potential mapping distributions at J point for 352 nodes were estimated from the 12-lead ECG, and an agreement with those estimated from 120 leads was assessed by a correlation coefficient (CC) (in percent). These estimates yielded very similar BSPM distributions, with a CC of 91.0% ± 8.1% (mean ± SD) for the entire test set and 94.1% ± 1.4%, 96.7% ± 0.8%, and 87.4% ± 10.3% for LAD, LCx, and RCA subgroups, respectively. Corresponding heart-surface potential distributions obtained by inverse solution correlated with a lower CC of 69.3% ± 18.0% overall and 73.7% ± 10.8%, 84.7% ± 1.1%, and 62.6% ± 21.8%, respectively, for subgroups. Bull's-eye displays of heart-surface potentials calculated from estimated BSPM distributions had an area of positive potentials that qualitatively corresponded, in general, with the underperfused territory suggested by SPECT images. For the LAD and LCx groups, all 9 ECG-derived bull's-eye images indicated the expected territory; for the RCA group, 6 of 9 ECG-derived images were as expected; 2 of 3 misclassified cases had very small ECG changes in response to coronary-artery occlusion, and their SPECT images showed indiscernible patterns. In conclusion, our findings demonstrate that noninvasive ECG imaging based on just the 12-lead ECG might provide useful estimates of the regions of myocardial ischemia that agree with those provided by scintigraphic techniques.     

Increased susceptibility for intrahepatic cholestasis of pregnancy and contraceptive-induced cholestasis in carriers of the 1331T〉C polymorphism in the bile salt export pump

AIM： To study the association of three common ABCB11 and ABCC2 polymorphisms （ABCB11： 1331T〉C→V444A; ABCC2： 3563T〉A → V1188E and 4544G 〉A → C1515Y） with intrahepatic cholestasis of pregnancy （ICP） and contraceptive-induced cholestasis （CIC）. METHODS： ABCB11 and ABCC2 genotyping data were available from four CIC patients and from 42 and 33 ICP patients, respectively. Allele-frequencies of the studied polymorphisms were compared with those in healthy pregnant controls and Caucasian individuals. Furthermore, serum bile acid levels were correlated with the presence or absence of the 1331 C allele. RESULTS： The ABCB11 1331T〉C polymorphism was significantly more frequent in cholestatic patients than in pregnant controls： C allele 76.2% （CI, 58.0-94.4） vs 51.3% （CI 35.8-66.7）, respectively （P = 0.0007）; and CC allele 57.1% （CI 36.0-78.3） vs 20% （CI 7.6-32.4）, respectively （P = 0.0065）. All four CIC patients were homozygous carriers of the C allele. In contrast, none of the studied ABCC2 polymorphism was overrepresented in ICP or CIC patients. Higher serum bile acid levels were found in carriers of the 1331CC genotype compared to carriers of the TT genotype. CONCLUSION： Our data support a role for the ABCB11 1331T〉C polymorphism as a susceptibility factor for the development of estrogen-induced cholestasis, whereas no such association was found for ABCC2. Serum bile acid and 7-glutamyl transferase levels might help to distinguish ABCB4- and ABCB11-related forms of ICP and CIC.     

Comparison of three treatment approaches to decreasing cardiovascular disease risk in nondiabetic insulin-resistant dyslipidemic subjects

The efficacy of fenofibrate (FEN), rosiglitazone (RSG), or a calorie-restricted diet (CRD) to reduce cardiovascular disease risk was compared in 37 overweight/obese insulin-resistant nondiabetic subjects. Insulin sensitivity, fasting lipids and lipoproteins, and postprandial plasma glucose, insulin, free fatty acid, and triglycerides were measured before and after 3 months of treatment with FEN, RSG, or CRD. Weight decreased in the CRD group, but did not change significantly after treatment with either drug. Insulin sensitivity improved significantly in the CRD- and RSG-treated groups, but to a greater extent in those administered RSG, without a significant difference comparing FEN treatment with the CRD. Total cholesterol was significantly lower after FEN and CRD treatment. Fasting plasma triglycerides decreased significantly in the FEN- and CRD-treated groups, but postprandial concentrations decreased in only FEN-treated subjects. Significant decreases in postprandial glucose and insulin were seen in only the RSG- and CRD-treated groups. FEN administration improved dyslipidemia in these subjects without changing insulin sensitivity, whereas insulin sensitivity was enhanced in RSG-treated patients without improvement in dyslipidemia. Weight loss in the CRD group led to improvements in both insulin sensitivity and dyslipidemia, but the change in the former was less than in RSG-treated patients, and improvement in lipid metabolism not as great as with FEN. In conclusion, there did not appear to be 1 therapeutic intervention that effectively treated all metabolic abnormalities present in these patients at greatly increased risk of cardiovascular disease.     

The end-of-life experience in long-term care: five themes identified from focus groups with residents, family members, and staff

PURPOSE: We designed this study to examine the end-of-life (EOL) experience in long-term care (LTC) based on input from key stakeholders. DESIGN AND METHODS: The study consisted of 10 homogeneous focus groups drawn from a purposive sample of LTC residents (2 groups; total n = 11), family caregivers (2 groups; total n = 19), paraprofessional staff (3 groups; total n = 20), and licensed/registered staff (3 groups; total n = 15) from five nursing homes and eight residential care/assisted living communities in North Carolina. We analyzed data by using grounded theory techniques to elicit manifest and latent themes. RESULTS: Five overarching themes emerged: (a) components of a good death in LTC, (b) normalcy of dying in LTC, (c) the role of relationships in the provision and receipt of care, (d) hospice contributions to care at the EOL in LTC, and (e) stakeholder recommendations for enhancing EOL care in these settings. Underlying these themes was one central category, closeness, based on physical proximity and frequency of contact. IMPLICATIONS: Findings suggest that promoting collaborative relationships among the four stakeholder groups, increasing social worker involvement, and removing barriers to hospice may enhance the EOL experience in LTC.     

Stroke Prevention in Atrial Fibrillation: Atrial Appendage Closure

The left atrial appendage (LAA) is the primary nonvalvular cause of cardioembolic stroke in patients with atrial fibrillation (AF). Warfarin and direct thrombin inhibitors such as dabigatran are presumed to prevent formation of LAA thrombus, and are first-line treatments to prevent ischemic stroke in AF. However, these medications carry many contraindications such as hemorrhage, and can interact with many drugs and supplements. Epicardial and endovascular techniques for occlusion of LAA are being explored, whether to mitigate the need for anticoagulation in patients at risk of bleeding or as a first-line therapy to reduce the risk of thromboembolic stroke. The purposes of this article are to 1) review the LAA structure and its potential contribution to ischemic stroke; 2) discuss the results of surgical and endovascular trials of LAA occlusion on risk of stroke and adverse events in AF patients; and 3) present early data on devices in development.     

Referral Patterns and Outcomes in Noncritically Ill Patients with Hospital-Acquired Acute Kidney Injury

Summary

Background and objectives

Despite modern treatment, the case fatality rate of hospital-acquired acute kidney injury (HA-AKI) is still high. We retrospectively described the prevalence and the outcome of HA-AKI without nephrology referral (nrHA-AKI) and late referred HA-AKI patients to nephrologists (lrHA-AKI) compared with early referral patients (erHA-AKI) with respect to renal function recovery, renal replacement therapy (RRT) requirement, and in-hospital mortality of HA-AKI.

Design, setting, participants, & measurements

Noncritically ill patients admitted to the tertiary care academic center of Lausanne, Switzerland, between 2004 and 2008 in the medical and surgical services were included. Acute kidney injury was defined using the Acute Kidney Injury Network (AKIN) classification.

Results

During 5 years, 4296 patients (4.12% of admissions) experienced 4727 episodes of HA-AKI during their hospital stay. The mean ± SD age of the patients was 61 ± 15 years with a 55% male predominance. There were 958 patients with nrHA-AKI (22.3%) and 2504 patients with lrHA-AKI (58.3%). RRT was required in 31% of the patients with lrHA-AKI compared with 24% of the patients with erHA-AKI. In the multiple risk factor analysis, compared with erHA-AKI, nrHA-AKI and lrHA-AKI were significantly associated with worse renal outcome and higher in-hospital mortality.

Conclusions

These data suggest that HA-AKI is frequent and the patients with nrHA-AKI or lrHA-AKI are at increased risk for in-hospital morbidity and mortality.