Sequences from higher primates orthologous to the human Xp/Yp telomere junction region reveal gross rearrangements and high levels of divergence

A high level of sequence polymorphism combined with linkage disequilibrium has created a limited number of highly diverged haplotypes across the human Xp/Yp telomere junction region. To gain insight into the unusual genetic characteristics of this region, we have examined the orthologous sequences in the common chimpanzee (Pan troglodytes ), the gorilla (Gorilla gorilla) and the orang-utan (Pongo pygmaeus). Divergence from the human Xp/Yp sequence is higher (average 2.6-fold) than that observed at other loci. The position of the human Xp/Yp telomere is unique, as additional sequences are present at this location in the other three species. These included an array of subterminal satellite in the chimpanzee and, in the gorilla a small interstitial array of telomere-like repeats followed by sequences with strong homology to the human 18p subterminal region. In the orang-utan, two alleles with different structures were identified. These differ by the presence or absence of a short interspersed nuclear element (SINE) sequence just proximal to long arrays of telomere-like repeat sequences that probably represent the proximal end of the orang-utan Xp/Yp telomere. In addition, a high level of sequence divergence between the two orang-utan structures was identified. This divergence is similar to that observed between the human Xp/Yp telomere-adjacent haplotypes. The high sequence divergence and evidence of gross rearrangements indicate that the Xp/Yp telomeric region has evolved faster than the rest of the genome.      

Cystoid macular oedema following cataract surgery: A review

Pseudophakic cystoid macular oedema (PCMO) remains a significant cause of compromised postoperative vision in contemporary cataract surgery. Well‐established risk factors include intraoperative complications such as posterior capsule rupture and preoperative factors including: diabetes mellitus, uveitis, retinal vein occlusion, epiretinal membrane. The role of topical glaucoma medications in PCMO continues to be debated. Current treatment strategies largely target suppression of inflammation. Topical NSAIDs remain the mainstay in prophylaxis and treatment of PCMO. Topical corticosteroids are commonly used as monotherapy or in combination with NSAIDs. Unfortunately, high‐quality trials are notably lacking for other PCMO treatment modalities such as: periocular corticosteroids, orbital floor triamcinolone, intravitreal triamcinolone, corticosteroid implants, intravitreal bevacizumab and pars‐plana vitrectomy. A lack of consistency in defining PCMO and resolution of PCMO explains why even large systematic reviews may come to contradictory conclusions. This review explores the varied contemporary evidence‐base in relation to the aetiology, diagnosis, prophylaxis and treatment of PCMO.     

The JNK inhibitor SP600129 enhances apoptosis of HCC cells induced by the tumor suppressor WWOX

BACKGROUND/AIMS: The FRA16D fragile site gene WWOX is a tumor suppressor that participates in p53-mediated apoptosis. The c-jun N-terminal kinase JNK1 interacts with WWOX and inhibits apoptosis. We investigated the function of WWOX in human hepatocellular carcinoma (HCC) and the effect of JNK inhibition on WWOX-mediated apoptosis. METHODS: Allelic imbalance on chromosome 16 was analyzed in 73 HCCs using 53 microsatellite markers. WWOX mRNA in HCC cell lines and primary HCCs was measured by real-time RT-PCR. Effects of WWOX on proliferation and apoptosis and the interaction between WWOX and JNK inhibition were examined. RESULTS: Loss on chromosome 16 occurred in 34 of 73 HCCs. Of 11 HCC cell lines, 2 had low, 7 intermediate, and 2 had high WWOX mRNA. Of 51 primary tumors, 23 had low WWOX mRNA. Forced expression of WWOX in SNU387 cells decreased FGF2-mediated proliferation and enhanced apoptosis induced by staurosporine and the JNK inhibitor SP600129. Conversely, knockdown of WWOX in SNU449 cells using shRNA targeting WWOX increased proliferation and resistance to SP600129-induced apoptosis. CONCLUSIONS: WWOX induces apoptosis and inhibits human HCC cell growth through a mechanism enhanced by JNK inhibition.     

Reversible self-association of a concentrated monoclonal antibody solution mediated by Fab-Fab interaction that impacts solution viscosity

Reversible self-association of a monoclonal antibody (MAb) in a high concentration formulation results in a solution with a high viscosity. The nature of the self-association of full-length as well as antibody fragments has been studied by rheometry. Chaotropic anions reduced solution viscosity more than kosmotropic anions, a result that can be explained by the Hofmeister series and the net charge of the MAb. The effect of strong chaotropes, such as urea and guanidine HCl at concentration below 300 mM on solution viscosity was also investigated. While the secondary and tertiary structure of the MAb was not altered, as determined by circular dichroism measurements, guanidine HCl reduced viscosity much more effectively than urea. Since urea is uncharged and guanidine HCl is monovalent, this study indicated that a charge effect may be a more important factor than the chaotropic nature of excipients in reducing solution viscosity by breaking network self-association of a MAb. To further understand which part of a MAb participates in this network self-association, a series of titration studies using the full-length MAb, F(ab')(2), and Fab fragments was conducted. From this study, the Fab was found to be the primary site of the network self-association.     

Combination of ECMO and cytokine adsorption therapy for severe sepsis with cardiogenic shock and ARDS due to Panton–Valentine leukocidin—positive <Emphasis Type="Italic">Staphylococcus aureus</Emphasis> pneumonia and H1N1

Sepsis-induced cardiogenic shock in combination with severe acute respiratory failure represents a life-threatening combination that is often refractory to the conventional methods of treatment. We describe the case of a 33-year-old patient who developed acute cardiovascular collapse and ARDS secondary to superinfection of Panton–Valentine leukocidin—positive Staphylococcus aureus and H1N1 pneumonia who underwent successful combination therapy for severe sepsis-related cardiomyopathy and respiratory failure using extracorporeal membrane oxygenation and cytokine adsorption therapy.     

Working profiles of dental hygienists in public and private practice in Finland and Norway

Abstract: Aim: The aim was to compare the working profiles of Finnish and Norwegian dental hygienists in public and private practice. To this end, we compared the procedures performed, the type of patients and the time devoted to different tasks. Subjects and methods: A questionnaire survey was originally conducted among a representative sample of dental hygienists in Finland (n = 595) and all authorized dental hygienists in Norway (n = 1 138) in 2004. The questionnaires collected data on the dental hygienists’ age, gender, year of graduation, working experience, work sector (private or public), working time spent on different activities and patient groups. The questionnaire also assessed how frequently the dental hygienists performed 25 different treatment measures. Results: The Norwegian dental hygienists spent 45.4% of their clinical time on check‐ups, whereas the Finns spent 49.9% of their time scaling. Dental hygienists in Finland and Norway working in the public sector spent 42.9% and 74.6% of their working time dealing with children and youth respectively. Conclusions: The working profiles of dental hygienists in Finland and Norway were quite similar, although differences in distribution by activities, type of patients and treatment measures do exist. The main activity of the dental hygienists was clinical work. The most commonly practised clinical activity among Finnish dental hygienists was scaling, and among Norwegians, check‐ups. Public dental hygienists in both countries dealt mainly with children and youths. Oral hygiene instruction was the most commonly reported treatment measure among both Finns and Norwegians.     

Viscosity behavior of high-concentration monoclonal antibody solutions: correlation with interaction parameter and electroviscous effects

The purpose of this work was to understand the viscosity behavior of high-concentration monoclonal antibody (mAb) solutions in a wide range of solution conditions and generate guidelines helpful to formulate products with manageable viscosity. The zeta potential and effective isoelectric point (pI) were determined from electrophoretic mobility measurements. High-frequency rheology studies characterized viscoelasticity at high concentrations. The interaction parameter (k(D) ) obtained from dynamic light scattering quantified intermolecular interactions. Circular dichroism characterized conformational stability upon change in solution pH. Except for mAb-1, all other mAb solutions were found to be more viscous at solution pHs closer to the molecular pI. For mAb-2, mAb-3, and mAb-10,the k(D) indicated intermolecular attractions at the pI, wherein the net molecular charge (Z) was zero, whereas repulsions dominated at pHs away from the pI. At the pI, Z and, hence, the charge-induced repulsions are minimal, whereas the charge distribution becomes most conspicuous. The resulting dominance of nonspecific attractive interactions at the pI increases the self-association or aggregation behavior of protein molecules, leading to a higher viscosity at the pI. mAb-1 is an exception to this general behavior. The k(D) could serve as a qualitative screening tool to predict high-concentration viscosity behavior, whereas the correlation with net charge was inconsistent. A higher negative k(D) generally resulted in a more viscous solution at high concentrations; however, direct quantitative assessment was not possible.