Evaluation of 99mTc-sulfonamide and sulfocoumarin derivatives for imaging carbonic anhydrase IX expression.

With the aim to prepare hypoxia tumor imaging agents, technetium(I) and rhenium(I) tricarbonyl complexes with dipyridylamine (L1 = N-{[1-(2,2-dioxido-1,2-benzoxathiin-6-yl)-1H-1,2,3-triazol-4-yl]methyl}-N-(2-pyridinylmethyl)-2-pyridinemethanamine; L3 = N-{[1-[N-(4-aminosulfonylphenyl)]-1H-1,2,3-triazol-4-yl]methyl}-N-(2-pyridinyl-methyl)-2-pyridinemethanamine), and iminodiacetate (H2L2 = N-{[1-(2,2-dioxido-1,2-benzoxathiin-6-yl)-1H-1,2,3-triazole-4-yl]methyl}-N-(carboxy-methyl)-glycine; H2L4 = N-{[1-[N-(4-aminosulfonylphenyl)]-1H-1,2,3-triazole-4-yl]methyl}-N-(carboxymethyl)-glycine) ligands appended to sulfonamide or sulfocoumarin carbonic anhydrase inhibitors were synthesized. The Re(I) complexes were characterized using 1H/13C NMR, MS, EA, and in one case the X-ray structure of [Et3NH][Re(CO)3(L2)] was obtained. As expected, the Re coordination geometry is distorted octahedral, with a tridentate iminodiacetate ligand in a fac arrangement dictated by the three strong-field CO ligands. Inhibition studies of human carbonic anhydrases (hCAs) showed that the Re sulfocoumarin derivatives were inactive against hCA-I, -II and -IV, but had moderate affinity for hCA-IX. The Re sulfonamides showed improved affinity against all tested hCAs, with [Re(CO)3(L4)]- being the most active and selective for the hCA-IX isoform. The corresponding 99mTc complexes were synthesized from fac-[99mTc(CO)3(H2O)3]+, purified by HPLC, and obtained with average 41-76% decay-corrected radiochemical yields and with >99% radiochemical purity. Uptake in HT-29 tumors at 1 h post-injection was highest for [99mTc(CO)3(L4)]- (0.14 ±â€¯0.10%ID/g) in comparison to [99mTc(CO)3(L1)]+ (0.06 ±â€¯0.01%ID/g), [99mTc(CO)3(L2)]- (0.03 ±â€¯0.00%ID/g), and [99mTc(CO)3(L3)]+ (0.07 ±â€¯0.03%ID/g). The uptake in tumors was further reduced at 4 h post-injection. For potential imaging application with single photon emission computed tomography, further optimization is needed to improve the affinity to hCA-IX and uptake in hCA-IX expressing tumors.

Severe adverse events associated with local anaesthesia in cataract surgery: 1†year national survey of practice and complications in the UK.

BACKGROUND: Recent years have seen a major change in practice of local anaesthesia (LA) for cataract surgery. AIMS: (1) To estimate current usage of LA techniques for cataract surgery, (2) to estimate the incidence of severe adverse events associated with each LA technique, (3) to compare with our previous 2003 study. METHODS: This was a prospective, observational study of routine practice. For 13 months in 2012-2013, the British Ophthalmological Surveillance Unit sent monthly mailings to all senior British ophthalmologists, asking for reports of 'potentially sight-threatening or life-threatening complications of LA for cataract surgery'. Current practice was assessed by questionnaire. RESULTS: Cataract surgery comprised 3.4% general anaesthesia, 92.5% LA alone and 4.1% LA with sedation. Techniques for the estimated 357 000 LA cataracts were: 8.8% peribulbar, 1.3% retrobulbar, 50.5% sub-Tenon's, 1.4% subconjunctival, 13.8% topical, 24.2% topical-intracameral LA. Severe sight-threatening complications included seven globe perforations, one cilioretinal artery occlusion and one severe corneal oedema. Severe life-threatening complications included one profound vasovagal episode, one silent myocardial infarction, one anaphylactic reaction and one supraventricular tachycardia. Under-reporting means that more complications probably occurred. CONCLUSIONS: There has been a large swing towards 'non-injection' LA in recent years. Serious adverse events were reported with all techniques except topical-intracameral and subconjunctival LA, though the incidence appears lower for 'non-injection' LA.

A generalized weighting regression-derived meta-analysis estimator robust to small-study effects and heterogeneity.

Heterogeneity and small-study effects are major concerns for the validity of meta-analysis. Although random effects meta-analysis provides a partial solution to heterogeneity, neither takes into account the presence of small-study effects, although they can rarely be ruled out with certainty. In this paper, we facilitate a better understanding of the properties of a recently described regression-based approach to deriving a meta-analysis estimator robust to small-study effects and unexplainable heterogeneity. The weightings of studies in the meta-analysis are derived algebraically for the regression model and compared with the weightings allocated to studies by fixed and random effects models. These weightings are compared in case studies with and without small-study effects. The presence of small-study effects causes pooled estimates from fixed and random effects meta-analyses to differ, potentially markedly, as a result of the different weights allocated to individual studies. Because random effects meta-analysis gives more weight to smaller studies, it becomes more vulnerable to the small-study effects. The regression approach gives heavier weight to the larger studies than either the fixed or random effects models, leading to its dominance in the estimated pooled effect. The weighting properties of the proposed regression-derived meta-analysis estimator are presented and compared with those of the standard meta-analytic estimators. We propose that there is much to recommend the routine use of this model as a reliable way to derive a pooled meta-analysis estimate that is robust to potential small-study effects, while still accommodating heterogeneity, even though uncertainty will often be considerably larger than for standard estimators.

Serious complications of local anaesthesia for cataract surgery: a 1 year national survey in the United Kingdom.

BACKGROUND: The techniques of sub-Tenon's, topical and topical-intracameral local anaesthesia (LA) have become common in routine practice. AIMS: This study aimed (i) to estimate the frequency of various LA techniques used in cataract surgery, (ii) to estimate the incidence of severe adverse events associated with each LA technique, and (iii) to document these adverse events. METHODS: This was a prospective, 13 month observational study of routine practice in the UK in 2002-2003. The British Ophthalmological Surveillance Unit sent a monthly mailing to UK ophthalmologists, asking for reports of "potentially sight-threatening or life-threatening complications of LA for cataract surgery". Current LA practice was assessed by questionnaire. RESULTS: Cataract surgery comprised 4.1% general anaesthesia, 92.1% LA without sedation and 3.9% LA with sedation. Of the estimated 375 000 LAs 30.6% were peribulbar, 3.5% retrobulbar, 42.6% sub-Tenon's, 1.7% sub-conjunctival, 9.9% topical and 11.0% topical-intracameral LA. "Potentially sight-threatening complications" were mostly associated with retrobulbar and peribulbar techniques and "potentially life-threatening" complications with all techniques except topical/intracameral LA. Eight neurological complications consistent with brainstem anaesthesia were reported: 7 with peribulbar or retrobulbar LA. Poisson regression analysis strongly indicated that rates vary with technique (p<0.001 for "potentially sight-threatening" complications, p = 0.03 for "neurological" complications). Because of likely under-reporting, further complications probably occurred during the survey period. CONCLUSIONS: This large survey found a lower rate of reported serious complications with sub-Tenon's, topical and topical-intracameral LA compared with retrobulbar and peribulbar techniques. These "newer" methods may be preferable for routine cataract surgery.