Sensitivity and specificity of human brain glutathione concentrations measured using short‐TE 1H MRS at 7 T

Although the MR editing techniques that have traditionally been used for the measurement of glutathione (GSH) concentrations in vivo address the problem of spectral overlap, they suffer detriments associated with inherently long TEs. The purpose of this study was to characterize the sensitivity and specificity for the quantification of GSH concentrations without editing at short TE. The approach was to measure synthetically generated changes in GSH concentrations from in vivo stimulated echo acquisition mode (STEAM) spectra after in vitro GSH spectra had been added to or subtracted from them. Spectra from five test subjects were synthetically altered to mimic changes in the GSH signal. To account for different background noise between measurements, retest spectra (from the same individuals as used to generate the altered data) and spectra from five other individuals were compared with the synthetically altered spectra to investigate the reliability of the quantification of GSH concentration. Using STEAM spectroscopy at 7 T, GSH concentration differences on the order of 20% were detected between test and retest studies, as well as between differing populations in a small sample (n = 5) with high accuracy (R² > 0.99) and certainty (p ≤ 0.01). Both increases and decreases in GSH concentration were reliably quantified with small impact on the quantification of ascorbate and γ‐aminobutyric acid. These results show the feasibility of using short‐TE ¹H MRS to measure biologically relevant changes and differences in human brain GSH concentration. Although these outcomes are specific to the experimental approach used and the spectral quality achieved, this study serves as a template for the analogous scrutiny of quantification reliability for other compounds, methodologies and spectral qualities. Copyright © 2016 John Wiley & Sons, Ltd.     

Corticosteroid treatment exacerbates nephrotic syndrome in a zebrafish model of magi2a knockout

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Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies

OBJECTIVE: To assess the efficacy and safety of rilonacept (Interleukin-1 [IL-1] Trap), a long-acting and potent inhibitor of IL-1, in patients with cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS). METHODS: Forty-seven adult patients with CAPS, as defined by mutations in the causative NLRP3 (CIAS1) gene and pathognomonic symptoms, were enrolled in 2 consecutive phase III studies. Study 1 involved a 6-week randomized double-blind comparison of weekly subcutaneous injections of rilonacept (160 mg) versus placebo. Study 2 consisted of 9 weeks of single-blind treatment with rilonacept (part A), followed by a 9-week, randomized, double-blind, placebo-controlled withdrawal procedure (part B). Primary efficacy was evaluated using a validated composite key symptom score. RESULTS: Forty-four patients completed both studies. In study 1, rilonacept therapy reduced the group mean composite symptom score by 84%, compared with 13% with placebo therapy (primary end point; P < 0.0001 versus placebo). Rilonacept also significantly improved all other efficacy end points in study 1 (numbers of multisymptom and single-symptom disease flare days, single-symptom scores, physician's and patient's global assessments of disease activity, limitations in daily activities, and C-reactive protein and serum amyloid A [SAA] levels). In study 2 part B, rilonacept was superior to placebo for maintaining the improvements seen with rilonacept therapy, as shown by all efficacy parameters (primary end point; P < 0.0001 versus placebo). Rilonacept was generally well tolerated; the most common adverse events were injection site reactions. CONCLUSION: Treatment with weekly rilonacept provided marked and lasting improvement in the clinical signs and symptoms of CAPS, and normalized the levels of SAA from those associated with risk of developing amyloidosis. Rilonacept exhibited a generally favorable safety and tolerability profile.     

Frequency and significance of complete atrioventricular block after coronary artery bypass grafting

Three hundred forty-eight consecutive patients were evaluated during 1985 and 1986 for the development of complete atrioventricular (AV) block after coronary artery bypass grafting. Cold (4 degrees) asanguineous potassium cardioplegia with temperature monitoring was used uniformly. AV block developed in 56 instances (16%). In 32 patients (group 1) the block was transient (less than 6 hours) and in 24 it was persistent (group 2). Left main coronary artery stenosis in conjunction with total obstruction of a dominant right coronary artery occurred more commonly in patients manifesting AV block (18 of 56, 32%) than in those without it (35 of 292, 12%) (p less than 0.05). Complete occlusion of a dominant right coronary artery was observed with equal frequency in patients with and without AV block. The presence of an ungraftable right coronary artery, however, was significantly more frequent in the AV block group: 16 of 37 (47%) vs 6 of 194 (3%) (p less than 0.01). Endarterectomy of the right coronary artery was performed in 8 of 24 patients (33%) with persistent AV block versus none in the patients with transient AV block (n = 32) or normal sinus rhythm postoperatively (n = 292) (p less than 0.0001). Persistent AV block (greater than 6 hours) was associated with myocardial infarction in 6 patients (25%) (p less than 0.05) and with low cardiac output in 18 patients (75%) (p less than 0.0001). In conclusion, AV block after myocardial revascularization was frequently associated with the presence of multivessel coronary disease and an ungraftable dominant right coronary artery. Persistent (greater than 6 hours) AV block was correlated with both perioperative myocardial infarction and low cardiac output.     

Arginine Vasotocin Gene Expression and Secretion during Osmotic Stimulation and Hemorrhagic Hypotension in Hens

In chickens, hyperosmolality stimulates the secretion of vasotocin (AVT) and up-regulates hypothalamic AVT gene expression. Hemorrhage, on the other hand, has not been considered an effective stimulus for AVT release in this species. The effects of acute osmotic stress and prolonged hemorrhagic hypotension on AVT gene expression and secretion were studied in White Leghorn hens. Conscious hens were osmotically stimulated by administering a single ip injection of 3MNaCl (5 ml/kg). Urethane-anesthetized hens were bled to a mean arterial pressure of 80–90 mm Hg and the pressure was maintained within this range by additional bleeding. A total of about 30% of the estimated blood volume was removed. Both experiments were terminated after 1 hr of stimulation. Plasma AVT levels in the hyperosmotic and hypovolemic hens were 4- and 2-fold higher, respectively, compared to controls. Hypothalamic AVT mRNA levels, detected by Northern blot analysis, were 2.5- and 2-fold higher in the osmotically stimulated and hypotensive groups, respectively, compared to control groups. As determined byin situhybridization, both osmotic stimulation and hypovolemia resulted in an increase in the number of AVT mRNA-containing neurons in the supraoptic and paraventricular nuclei. Our results indicate that, under the conditions used, hypotension and hyperosmolality are equally effective in stimulating AVT gene expression and secretion of AVT.     

Controlled trial of faecal occult blood testing in the detection of colorectal cancer

20 525 patients from general practitioners' lists were randomly allocated into test and control groups. The 10 253 test subjects were invited to perform haemoccult faecal occult blood testing over 3 days. 3613 (36 . 8%) of the 9807 who received their invitations completed the test. Compliance was improved by direct invitation from the general practitioner and by prior health education by letter or interview. 77 people (2 . 1%) had a positive test result, and 50% of these on investigation had neoplastic disease--12 had invasive carcinomas (9 Dukes' stage A, 2 stage B, 1 stage C) and 27 had 40 adenomas (12 over 2 cm, 2 of which contained areas of severe dysplasia). In the year following the screening test 1 carcinoma (stage C) has presented in the group which accepted the test, and 10 carcinomas (4 stage B, 4 stage C, 2 stage D) have presented in the control group. This respresents a 3 . 6 times greater detection rate per 1000 persons in the test group than in the control group. Only 8 adenomas have presented in the control and non-responding groups. Fibreoptic sigmoidoscopy identified the 10 carcinomas within its range and 39 of the 40 adenomas. Double-contrast barium enema identified only 9 of the 12 carcinomas and 24 (62%) of the 40 adenomas. All 3 carcinomas not identified by barium enema were polypoid Dukes' stage-A lesions.