A case‐control study and meta‐analysis reveal the association between COX‐2 G‐765C polymorphism and primary end‐stage hip and knee osteoarthritis

Background

Osteoarthritis (OA) is a popular arthrosis featured as pain, limited joint activity, and deformity. Cyclooxygenase‐2 (COX‐2) has been reported to be up‐regulated in arthritic tissues and is integral to the progression of osteoarthritis (OA). Previous studies showed the COX‐2 promoter G‐765C polymorphism could influence COX‐2 expression. However, the relationship between the variant and OA risk is contrasting.

Methods

We conducted a case‐control study with 196 primary end‐stage hip and knee OA cases and 196 controls in a Chinese Han population. Subsequently, we integrated this case‐control study in a meta‐analysis to acquire greater statistical power. The results from our case‐control study using MassARRAY genotyping technology and binary logistic regression statistical methods.

Results

The variant carriers in the Chinese Han population had a lower primary end‐stage hip and knee OA susceptibility (C vs G: OR = 0.350, 95%CI: 0.154‐0.797, P = .012; GC vs GG: adjusted OR = 0.282, 95%CI: 0.118‐0.676, P = .005). Stratification studies indicated that a higher GC frequency in women decreased not only knee OA susceptibility but also unilateral knee OA risk. The meta‐analysis showed that the variant exhibited a significantly decreased OA risk through comparisons involving allelic, homozygous, heterozygous, and dominant models.

Conclusion

Our findings suggest that the COX‐2 G‐765C polymorphism exerts a protective effect against primary end‐stage knee osteoarthritis in a female Chinese Han population.

     

Wedge-shaped intrahepatic cholangiocarcinoma:MRI<+>–<+>pathologic correlation

On magnetic resonance imaging (MRI) studies, wedge-shaped areas of signal abnormality noted in association with liver lesions have been attributed to secondary phenomena and are said to be substantially larger than the actual tumor. We describe the MRI and pathological appearance of a wedge-shaped cholangiocarcinoma. In cases where therapy might be affected, biopsy of wedge-shaped MRI abnormalities associated with hepatic malignancy should be considered for accurate tumor staging. Received: 23 December 1994/Accepted: 25 January 1995     

Color Doppler imaging of the gallbladder wall in acute cholecystitis: sonographic<+>–<+>pathologic correlation

Background: The purpose of this study was to evaluate the usefulness of color Doppler imaging (CDI) in suspected cases of acute cholecystitis. Methods: Twenty-two patients suspected of having acute cholecystitis were prospectively evaluated over a 12-month period using gray-scale and color Doppler technique. Gallbladder wall thickness was greater than 2 mm in all patients included in the study. Pathologic correlation was obtained in 17 patients, with clinical or sonographic follow-up in five for a period of 6<+>–/011001/months. CDI was considered positive only if the mid to fundal wall demonstrated flow. Sonographic Murphy's sign and laboratory values were recorded. Results: Eight patients had acute cholecystitis. All had positive color Doppler flow. Wall thickness in these patients ranged between 4 and 10 mm. Three patients with necrotizing acute cholecystitis had no flow within 6<+>–<+>8-mm walls. Six patients with pathologically proven chronic cholecystitis had no evidence of increased flow within thickened walls. Five patients with presumed chronic cholecystitis (thickened wall without increased color flow) were treated medically, and their symptoms resolved. CDI was more sensitive in predicting acute cholecystitis than was the sonographic Murphy's sign and/or laboratory values. Conclusion: CDI demonstrates hyperemic changes in thickened gallbladder walls and is an important adjunct in the diagnosis of acute cholecystitis. Received: 3 February 1995/Accepted: 24 March 1995     

Involvement of α2‐adrenoceptors,imidazoline, and endothelin‐A receptors in the effect of agmatine on morphine and oxycodone‐induced hypothermia in mice

Potentiation of opioid analgesia by endothelin‐A (ET_A) receptor antagonist, BMS182874, and imidazoline receptor/α₂‐adrenoceptor agonists such as clonidine and agmatine are well known. It is also known that agmatine blocks morphine hyperthermia in rats. However, the effect of agmatine on morphine or oxycodone hypothermia in mice is unknown. The present study was carried out to study the role of α₂‐adrenoceptors, imidazoline, and ET_A receptors in morphine and oxycodone hypothermia in mice. Body temperature was determined over 6 h in male Swiss Webster mice treated with morphine, oxycodone, agmatine, and combination of agmatine with morphine or oxycodone. Yohimbine, idazoxan, and BMS182874 were used to determine involvement of α₂‐adrenoceptors, imidazoline, and ET_A receptors, respectively. Morphine and oxycodone produced significant hypothermia that was not affected by α₂‐adrenoceptor antagonist yohimbine, imidazoline receptor/α₂ adrenoceptor antagonist idazoxan, or ET_A receptor antagonist, BMS182874. Agmatine did not produce hypothermia; however, it blocked oxycodone but not morphine‐induced hypothermia. Agmatine‐induced blockade of oxycodone hypothermia was inhibited by idazoxan and yohimbine. The blockade by idazoxan was more pronounced compared with yohimbine. Combined administration of BMS182874 and agmatine did not produce changes in body temperature in mice. However, when BMS182874 was administered along with agmatine and oxycodone, it blocked agmatine‐induced reversal of oxycodone hypothermia. This is the first report demonstrating that agmatine does not affect morphine hypothermia in mice, but reverses oxycodone hypothermia. Imidazoline receptors and α₂‐adrenoceptors are involved in agmatine‐induced reversal of oxycodone hypothermia. Our findings also suggest that ET_A receptors may be involved in blockade of oxycodone hypothermia by agmatine.     

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.     

Impact of polymorphisms of the major histocompatibility complex class II,interleukin‐10, tumor necrosis factor‐α and cytotoxic T‐lymphocyte antigen‐4 genes on inhibitor development in severe hemophilia A

Summary. Background: Approximately 25% of severe hemophilia A (HA) patients develop antibodies to factor VIII protein. Patients: In the present case‐controlled cohort study, 260 severely affected, mutation‐type‐matched HA patients were studied for association of human leukocyte antigen (HLA) class II molecules and polymorphisms in the genes encoding interleukin‐10 (IL‐10), tumor necrosis factor‐α (TNF‐α) and cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) and development of inhibitors. Results: Our results demonstrate a higher frequency of DRB1*15 and DQB1*0602 alleles as well as of the haplotype DRB1*15/DQB1*0602 in inhibitor patients [odds ratio (OR) 1.9; P < 0.05]. In TNF‐α, the A allele of the ?308G>A polymorphism was found with higher frequency in the inhibitor cohort (0.22 vs. 0.13, OR 1.80). This finding was more pronounced for the homozygous A/A genotype (OR 4.7). For IL‐10, the ?1082G allele was observed more frequently in patients with inhibitors (0.55 vs. 0.43; P = 0.008). The functional cytokine phenotype was determined for the first time, on the basis of the genetic background, and this showed that 12% of patients with inhibitors were high‐TNF‐α/high‐IL‐10 producers, as compared with 3% of non‐inhibitor patients (OR 4.4). A trend for a lower frequency of the A allele of the CT60 polymorphism in CTLA‐4 was found in inhibitor patients (0.42 vs. 0.50). Conclusions: In conclusion, the reported data clearly highlighted the participation of HLA molecules in inhibitor formation in a large cohort of patients. The higher frequencies of the ?308G>A polymorphism in TNF‐α and ?1082A>G in IL‐10 in inhibitor patients confirmed the earlier published data. The CT60 single‐nucleotide polymorphism in CTLA‐4 is of apparently less importance.     

Comparison of behavioral,neuroprotective, and proinflammatory cytokine modulating effects exercised by (+)‐cis‐EC and (−)‐cis‐EC stereoisomers in a PTZ‐induced kindling test in mice

Epoxy‐carvone (EC) has chiral centers that allow generation of stereoisomers, including (+)‐cis‐EC and (?)‐cis‐EC, whose effects in the kindling tests have never been studied. Accordingly, this study aims to comparatively investigate the effect of stereoisomers (+)‐cis‐epoxy‐carvone and (?)‐cis‐epoxy‐carvone on behavioral changes measured in scores, in the levels of cytokines (IL‐1β, IL‐6, and TNFα) and neuronal protection in the face of continuous treatment with pentylenetetrazol. Swiss mice were divided into five groups (n = 10), receiving vehicle, (+) – cis‐EC, (?) – cis‐EC (both at the dose of 30 mg/kg), and diazepam (4 mg/kg). Thirty minutes after the respective treatment was administered to the animals one subconvulsive dose of PTZ (35 mg/kg). Seven subconvulsives treatments were made on alternate days, in which each treatment several parameters were recorded. In the eighth treatment, the animals receiving the highest dose of PTZ (75 mg/kg) and were sacrificed for quantification of cytokines and histopathologic analysis. All drugs were administered by intraperitoneal route. In the kindling test, (+)‐cis‐EC and (?)‐cis‐EC reduced the average scores. The stereoisomer (+)‐cis‐EC decreased levels of proinflammatory cytokines IL‐1β, IL‐6, and TNFα, whereas comparatively (?)‐cis‐EC did not reduce IL‐1β levels. Histopathological analysis of the mice hippocampi undergoing this methodology showed neural protection for treated with (+)‐cis‐EC. The results suggest that the anticonvulsant effect of (+)‐cis‐EC possibly takes place due to reduction of proinflammatory cytokines involved in the epileptogenic process, besides neuronal protection, yet further investigation of the mechanisms involved is required.     

Synthesis and characterization of poly(glycerol‐co‐sebacate‐co‐ε‐caprolactone) elastomers

In this study, poly(glycerol‐co‐sebacate‐co‐ε‐caprolactone) (PGSCL) elastomers were synthesized for the first time from the respective monomers. The structural analysis of PGSCL elastomers by nuclear magnetic resonance (¹H‐NMR) and Fourier transform infrared spectroscopy (FTIR) revealed that the elastomers have a high number of hydrogen bonds and crosslinks. X‐ray diffraction (XRD) and thermal analysis indicated an amorphous state. Differential scanning calorimetry (DSC) analysis showed that the elastomers has a glass transition temperature (T_g) of –36.96°C. The Young's modulus and compression strength values were calculated as 46.08 MPa and 3.192 MPa, respectively. Calculations based on acid number and end groups analysis revealed a number average molecular weight of 148.15 kDa. Even though the foaming studies conducted by using supercritical CO₂ resulted in a porous structure; the obtained morphology tended to disappear after 48 h, leaving small cracks on the surface. This phenomenon was interpreted as an indication of self‐healing due to the high number of hydrogen bonds. The PGSCL elastomers synthesized in this study are flexible, robust to compression forces and have self‐healing capacity. Thanks to good biocompatibility and poor cell‐adhesion properties, the elastomers may find diverse applications where a postoperative adhesion barrier is required. Copyright © 2013 John Wiley & Sons, Ltd.     

Transfusion‐transmitted CMV infection – current knowledge and future perspectives

Transmission of human cytomegalovirus (CMV) via transfusion (TT‐CMV) may still occur and remains a challenge in the treatment of immunocompromised CMV‐seronegative patients, e.g. after stem cell transplantation, and for low birthweight infants. Measures to reduce the risk of TT‐CMV have been evaluated in clinical studies, including leucocyte depletion of cellular blood products and/or the selection of CMV‐IgG‐negative donations. Studies in large blood donor cohorts indicate that donations from newly CMV‐IgG‐positive donors should bear the highest risk for transmitting CMV infections because they contain the highest levels of CMV‐DNA, and early CMV antibodies cannot neutralise CMV. Based on this knowledge, rational strategies to reduce the residual risk of TT‐CMV using leucoreduced blood products could be designed. However, there is a lack of evidence that CMV is still transmitted by transfusion of leucoreduced units. In low birthweight infants, most (if not all) CMV infections are caused by breast milk feeding or congenital transmission rather than by transfusion of leucoreduced blood products. For other patients at risk, no definitive data exist about the relative importance of alternative transmission routes of CMV compared to blood transfusion. As a result, only the conduction of well‐designed studies addressing strategies to prevent TT‐CMV and the thorough examination of presumed cases of TT‐CMV will achieve guidance for the best transfusion regimen in patients at risk.