An evaluation of a high‐pressure 11CO carbonylation apparatus

[¹¹C]Carbon monoxide (¹¹CO) is a versatile building block for the synthesis of Positron Emission Tomography (PET) radioligands. However, the difficulty of trapping ¹¹CO in a small solvent volume has limited its utility. We here report an evaluation of a simple, fully automated high‐pressure synthesizer prototype for the use in ¹¹C‐carbonylation reactions. [¹¹C]Carbon monoxide was easily prepared by online reduction of [¹¹C]carbon dioxide using either Mo(s) or Zn(s) as the reducing agent. The conversion yield of ¹¹CO was >99% when zinc was used as the reducing agent, and the corresponding value for Mo was approximately 71%. When the Zn or Mo column was constantly kept under inert atmosphere, no significant decrease in reducing properties was observed for more than 100 ¹¹CO productions. However, in our hands, Mo reductant was much easier to service. A total of nine functional groups were successfully radiolabeled using the ¹¹CO synthesizer prototype. All measured radiochemical yields exceeded 37%, and the ¹¹CO trapping efficiency was generally above 90%, except for the Suzuki coupling where the trapping efficiency was 80%. This high‐pressure synthesizer using [¹¹C]carbon monoxide as the labeling precursor is easy to operate allowing for ¹¹C‐carbonylation reactions to be performed in a high yield and in a routinely fashion.     

Jejunal secretion of secretory immunoglobulins and gliadin antibodies in celiac disease

The aim of this study was to determine the secretion of secretory immunoglobulins and gliadin antibodies in the small bowel in celiac disease. Twenty-four patients were investigated by perfusion of a defined jejunal segment. Four of the patients studied had a serum IgA deficiency and had no measurable amounts of secretory IgA in the perfusion fluid. The other patients demonstrated a significant increase in the jejunal concentration of secretory IgA (median 28.5 mg/liter) compared with healthy controls (median 16 mg/liter,N=16) and of IgM, celiac (median 12.3 mg/liter) compared to healthy controls (median 6.8 mg/liter,N=16). Jejunal IgA gliadin antibodies were detected in all patients except those with an IgA deficiency. All patients had jejunal IgM gliadin antibodies, but none of the patients had measurable jejunal IgG gliadin antibodies. A positive correlation was detected between serum and jejunal IgA gliadin antibody levels in the celiac patients, (P<0.01). Calculation of the ratio between gliadin antibodies and total levels of IgA and IgM in serum and jejunal perfusate demonstrated that the jejunal synthesis of gliadin antibodies of IgA and IgM type is both more pronounced and persistent than the systemic humoral immune response to gliadin.This work was supported by grants from the Swedish Medical Research Council, the Swedish Life Insurance Companies' Trust for Medical Research, and Th.C. Berghs Foundation and Pharmacia AB, Sweden.     

Development of the Gambling Disorder Identification Test: Results from an international Delphi and consensus process

ObjectivesDiverse instruments are used to measure problem gambling and Gambling Disorder intervention outcomes. The 2004 Banff consensus agreement proposed necessary features for reporting gambling treatment efficacy. To address the challenge of including these features in a single instrument, a process was initiated to develop the Gambling Disorder Identification Test (GDIT), as an instrument analogous to the Alcohol Use Disorders Identification Test and the Drug Use Disorders Identification Test.MethodsGambling experts from 10 countries participated in an international two‐round Delphi (n = 61; n = 30), rating 30 items proposed for inclusion in the GDIT. Gambling researchers and clinicians from several countries participated in three consensus meetings (n = 10; n = 4; n = 3). User feedback was obtained from individuals with experience of problem gambling (n = 12) and from treatment‐seekers with Gambling Disorder (n = 8).ResultsTen items fulfilled Delphi consensus criteria for inclusion in the GDIT (M ≥ 7 on a scale of 1–9 in the second round). Item‐related issues were addressed, and four more items were added to conform to the Banff agreement recommendations, yielding a final draft version of the GDIT with 14 items in three domains: gambling behavior, gambling symptoms and negative consequences.ConclusionsThis study established preliminary construct and face validity for the GDIT.     

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.     

Electrocardiogram signal variance analysis in the diagnosis of coronary artery disease—A comparison with exercise stress test in an angiographically documented high prevalence population

Variance electrocardiography (variance ECG) is a new resting procedure for detection of coronary artery disease (CAD). The method measures variability in the electrical expression of the depolarization phase induced by this disease. The time-domain analysis is performed on 220 cardiac cycles using high-fidelity ECG signals from 24 leads, and the phase-locked temporal electrical heterogeneity is expressed as a nondimensional CAD index (CAD-I) with the values of 0–150. This study compares the diagnostic efficiency of variance ECG and exercise stress test in a high prevalence population. A total of 199 symptomatic patients evaluated with coronary angiography was subjected to variance ECG and exercise test on a bicycle ergometer as a continuous ramp. The discriminant accuracy of the two methods was assessed employing the receiver operating characteristic curves constructed by successive consideration of several CAD-I cutpoint values and various threshold criteria based on ST-segment depression exclusively or in combination with exertional chest pain. Of these patients, 175 with CAD (≥ 50% luminal stenosis in 1 + major epicardial arteries) presented a mean CAD-I of 88 ± 22, compared with 70 ± 21 in 24 nonaffected patients (p < 0.01). Variance ECG provided a stochastically significant discrimination (p < 0.01) which was matched by exercise test only when chest pain variable was added to ST-segment depression as a discriminating criterion. Even then, the exercise test diagnosed single-vessel disease with a significantly lower sensitivity. At a cutpoint of CAD-I ≥ 70, compared with ST-segment depression ≥ 1 mm combined with exertional chest pain, the overall sensitivity of variance ECG was significantly higher (p < 0.01) than that of exercise test (79 vs. 48 %). When combined, the two methods identified 93% of coronary angiography positive cases. Variance ECG is an efficient diagnostic method which compares favorably with exercise test for detection of CAD in high prevalence population.     

No effect of risedronate on femoral periprosthetic bone loss following total hip arthroplasty: A 4-year follow-up of 61 patients in a double-blind,randomized placebo-controlled trial

Background and purpose

We have previously shown that during the first 2 years after total hip arthroplasty (THA), periprosthetic bone resorption can be prevented by 6 months of risedronate therapy. This follow-up study investigated this effect at 4 years.

Patients and methods

A single-center, double-blind, randomized placebo-controlled trial was carried out from 2006 to 2010 in 73 patients with osteoarthritis of the hip who were scheduled to undergo THA. The patients were randomly assigned to receive either 35 mg risedronate or placebo orally, once a week, for 6 months postoperatively. The primary outcome was the percentage change in bone mineral density (BMD) in Gruen zones 1 and 7 in the proximal part of the femur at follow-up. Secondary outcomes included migration of the femoral stem and clinical outcome scores.

Results

61 of the 73 patients participated in this 4-year (3.9- to 4.1-year) follow-up study. BMD was similar in the risedronate group (n = 30) and the placebo group (n = 31). The mean difference was −1.8% in zone 1 and 0.5% in zone 7. Migration of the femoral stem, the clinical outcome, and the frequency of adverse events were similar in the 2 groups.

Interpretation

Although risedronate prevents periprosthetic bone loss postoperatively, a decrease in periprosthetic BMD accelerates when therapy is discontinued, and no effect is seen at 4 years. We do not recommend the use of risedronate following THA for osteoarthritis of the hip.Adaptive bone remodeling around the femoral stem following total hip arthroplasty (THA) results in regional loss of bone mass, especially in proximal parts of the femur—most of which takes place within the first postoperative year (Bodén et al. 2006, Sköldenberg et al. 2006). Periprosthetic bone loss may predispose to periprosthetic fracture, aseptic loosening, and difficulties at revision surgery (Lindahl 2007, Streit et al. 2011, Sköldenberg et al. 2014).The bisphosphonate (BP) risedronate has been used successfully to prevent osteoporotic fractures, mainly in the hip and vertebrae, by inhibiting osteoclast activity (McClung et al. 2001). In recent years, the possible use of BPs to prevent or ameliorate periprosthetic adaptive bone resorption, osteolysis, and implant migration has been investigated thoroughly in animal models and humans. The short-term results of several studies showing the effects of postoperative BP treatment in reducing periprosthetic bone loss up to a year after the arthroplasty have already been published (Venesmaa et al. 2001, Wilkinson et al. 2001, Hennigs et al. 2002, Wilkinson et al. 2005, Arabmotlagh et al. 2006).We have previously found that risedronate given once a week for 6 months after THA reduces periprosthetic bone resorption around an uncemented femoral stem in the first and second postoperative year (Sköldenberg et al. 2011). We now report the 4-year outcome in the same cohort.