Antibacterial and β‐Lactamase Inhibitory Activity of Monocyclic β‐Lactams

Due to the widespread emergence of resistant bacterial strains, an urgent need for the development of new antibacterial agents with novel modes of action has emerged. The discovery of naturally occurring monocyclic β‐lactams in the late 1970s, mainly active against aerobic Gram‐negative bacteria, has introduced a new approach in the design and development of novel antibacterial β‐lactam agents. The main goal was the derivatization of the azetidin‐2‐one core in order to improve their antibacterial potency, broaden their spectrum of activity, and enhance their β‐lactamase stability. In that respect, our review covers the updates in the field of monocyclic β‐lactam antibiotics during the last three decades, taking into account an extensive collection of references. An overview of the relationships between the structural features of these monocyclic β‐lactams, classified according to their N‐substituent, and the associated antibacterial or β‐lactamase inhibitory activities is provided. The different paragraphs disclose a number of well‐established classes of compounds, such as monobactams, monosulfactams, monocarbams, monophosphams, nocardicins, as well as other known representative classes. Moreover, this review draws attention to some less common but, nevertheless, possibly important types of monocyclic β‐lactams and concludes by highlighting the recent developments on siderophore‐conjugated classes of monocyclic β‐lactams.     

Effects of variation in the human α2A‐ and α2C‐adrenoceptor genes on cognitive tasks and pain perception

Background: The mechanisms underlying interindividual variability in pain perception and cognitive responses are undefined but highly heritable. α_2C‐ and α_2A‐adrenergic receptors regulate noradrenergic activity and are important mediators of pain perception and analgesia. We hypothesized that common genetic variants in these genes, particularly the ADRA2C 322–325 deletion variant, affect pain perception or cognitive responses. Methods: We studied 73 healthy subjects (37 Caucasians and 36 African–Americans) aged 25.4 ± 4.6 years. Pain response to a cold pressor test was measured using a 10 cm visual analog scale and again on the next day, after three infusions of the selective α₂‐agonist dexmedetomidine. Standardized cognitive tests were administered at baseline and after each infusion. The contribution of ADRA2C deletion genotype, dexmedetomidine concentration, and other covariates to pain perception and cognitive responses was determined using multiple linear regression models. Secondary analysis examined the effects of ADRA2A and other ADRA2C variants on pain perception. Results: ADRA2C Del homozygotes had higher pain scores in response to cold at baseline (6.3 ± 1.8 cm) and after dexmedetomidine (5.6 ± 2.2 cm) than insertion allele carriers (4.6 ± 2.1 cm [baseline] and 3.8 ± 1.9 cm [after dexmedetomidine]; adjusted P‐values = 0.019 and 0.004, respectively). Cognitive responses were unrelated to ADRA2C Ins/Del genotype. None of the other ADRA2A and ADRA2C variants was significantly related to cold pain sensitivity before dexmedetomidine; after dexmedetomidine, ADRA2A rs1800038 was marginally associated (P = 0.03). Conclusion: The common ADRA2C del322–325 variant affected pain perception before and after dexmedetomidine but did not affect other cognitive responses, suggesting that it contributes to interindividual variability in pain perception.     

An αIIb mutation in patients with Glanzmann thrombasthenia located in the N‐terminus of blade 1 of the β‐propeller (Asn2Asp) disrupts a calcium binding site in blade 6

Summary. Background: Studies of Glanzmann thrombasthenia (GT)‐causing mutations has generated invaluable information on the formation and function of integrin αIIbβ₃. Objective: To characterize the mutation in four siblings of an Israeli Arab family affected by GT, and to analyze the relationships between the mutant protein structure and its function using artificial mutations. Methods and Results: Sequencing disclosed a new A97G transversion in the αIIb gene predicting Asn2Asp substitution at blade 1 of the β‐propeller. Alignment with other integrin α subunits revealed that Asn2 is highly conserved. No surface expression of αIIbβ₃ was found in patients’ platelets and baby hamster kidney (BHK) cells transfected with mutated αIIb and WT β₃. Although the αIIbβ₃ was formed, the mutation impaired its intracellular trafficking. Molecular dynamics simulations and modeling of the αIIbβ₃ crystal indicated that the Asn2Asp mutation disrupts a hydrogen bond between Asn2 and Leu366 of a calcium binding domain in blade 6, thereby impairing calcium binding that is essential for intracellular trafficking of αIIbβ₃. Substitution of Asn2 to uncharged Ala or Gln partially decreased αIIbβ₃ surface expression, while substitution by negatively or positively charged residues completely abolished surface expression. Unlike αIIbβ₃, αVβ₃ harboring the Asn2Asp mutation was surface expressed by transfected BHK cells, which is consistent with the known lower sensitivity of αVβ₃ to calcium chelation compared with αIIbβ₃. Conclusion: The new GT causing mutation highlights the importance of calcium binding domains in the β‐propeller for intracellular trafficking of αIIbβ₃. The mechanism by which the mutation exerts its deleterious effect was elucidated by molecular dynamics.     

Coagulopathy and functional hyposplenism during an episode of thrombotic thrombocytopenic purpura in a HgbS/β+‐thalassemia patient

We report a case of TTP in a sickle cell/β+‐thalassemia heterozygote with nonspecific complaints and a evidence of hemolysis, initially attributed to sickle crisis. Included in this case is a discussion of the development of functional hyposplenism, a rarely reported complication, limitation of ADAMTS‐13 in diagnosis, and the use of platelet transfusion.     

Determination of α-amylase in biological fluids using a new substrate (β-2-chloro-4-nitrophenyl-maltopentaoside)

A novel substrate, β-2-chloro-4-nitrophenylmaltopentaoside(βCNPG5), was used for the enzyme-coupled determination of α-amylase in biological fluids. It was hydrolyzed specifically by α-amylase to about 90% producing β-2-chloro-4-nitrophenylmaltoside (βCNPG2) and maltotriose. Under the assay conditions, the absorption of 2-chloro-4-nitrophenol (CNP) generated by the secondary reaction of α-glucosidase and β-glucosidase as auxiliary enzymes is about twice the absorption of 4-nitrophenol (PNP), which is the end product currently measured in some α-amylase assay methods. The sensitivity of the assay using βCNPG5 was thus much higher than that using 4-nitrophenyl-maltopentaoside (PNPG5) as substrate. The absorption of CNP did not fluctuate with temperature or with pH between 6.8 and 7.2, which are the conditions normally used for determination of amylase activity in biological fluids.     

β‐Blocker in Post‐Myocardial Infarct Survivors with Preserved Left Ventricular Systolic Function

Background: Long‐term β‐blockade therapy is beneficial in post‐myocardial infarct (MI) patients with left ventricular (LV) dysfunction; nevertheless, its benefit in post‐MI patients with preserved LV function remains unclear. The objective of this study is to investigate the effects of long‐term β‐blockade therapy on the clinical outcomes in post‐MI patients with preserved LV function. Hypothesis: The beneficial effects of long‐term β‐blockade therapy in post‐MI patients with impaired LV function may extend to those with preserved LV function. Methods: Of 617 consecutive post‐MI patients referred for cardiac rehabilitation program, 208 patients (age: 62.7 ± 0.8 years; male: 76%) with preserved LV function (ejection fraction ≥ 50%), negative exercise stress test, and on angiotensin‐converting enzyme inhibition were studied. Results: Baseline characteristics were comparable between patients on β‐blocker (n = 154) and not on β‐blocker (n = 54). After a mean follow‐up of 58.5 ± 2.7 months, 14 patients not on β‐blocker (26%) and 14 patients on β‐blocker (9%) died with hazard ratio (HR) of 2.5 (95% confidence interval [CI]: 1.25–6.42, P = 0.01). Likewise, patients not on β‐blocker had a higher incidence of cardiac death (HR: 3.0, 95% CI: 1.07–12.10, P = 0.04), and non‐sudden cardiac death (HR: 10.1, 95% CI: 1.82–89.65, P = 0.01), but not sudden cardiac death compared with patients on β‐blocker (HR: 1.6, 95% CI: 0.34–7.61, P = 0.54). A Cox regression analysis revealed that only advanced age (≥75 years; HR: 2.55, 95% CI: 1.18–5.49, P = 0.02) and the absence of β‐blocker (HR: 2.41, 95% CI: 1.14–5.09, P = 0.02) were independent predictors for mortality. Conclusion: β‐blocker use was associated with a decrease in overall mortality and cardiac death in post‐MI patients with preserved LV function. (PACE 2010; 33:675–680)     

Thalassemia trait and arterial thromboembolic events: a systematic review and a meta‐analysis of the literature

Summary. Background: An increased risk of venous thromboembolic events has been reported in thalassemic patients, in particular in patients with thalassemia intermedia. The association between β‐thalassemia trait and atherothrombotic cardiovascular events is not well established. Methods: In a systematic review and meta‐analysis of the literature, we evaluated the association between β‐thalassemia trait and arterial cardiovascular disease. Studies were identified from the MEDLINE and EMBASE (until July 2010) electronic databases. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with a random‐effects model. Statistical heterogeneity was evaluated with the I² statistic. Results: Of the 354 identified articles, eight case–control studies were eligible for the analysis. β‐Thalassemia trait was associated with a reduced risk of arterial cardiovascular disease (OR 0.45; 95% CI 0.45–0.60). Heterogeneity among studies was low (I² = 13%). The protective effect of β‐thalassemia trait was confined to male patients (OR 0.39; 95% CI 0.24–0.62), and was not observed in female subjects (OR 0.89; 95% CI 0.52–1.53). Conclusions: β‐Thalassemia trait may act as a protective factor against the development of arterial cardiovascular and cerebrovascular disease in male subjects. Larger prospective studies are necessary to confirm these preliminary findings and to further investigate the mechanisms underlying this protective effect.