Working memory training and brain structure and function in extremely preterm or extremely low birth weight children

This study in children born extremely preterm (EP; <28 weeks’ gestational age) or extremely low birth weight (ELBW; <1,000 g) investigated whether adaptive working memory training using Cogmed® is associated with structural and/or functional brain changes compared with a placebo program. Ninety‐one EP/ELBW children were recruited at a mean (standard deviation) age of 7.8 (0.4) years. Children were randomly allocated to Cogmed or placebo (45‐min sessions, 5 days a week over 5–7 weeks). A subset had usable magnetic resonance imaging (MRI) data pretraining and 2 weeks posttraining (structural, n = 48; diffusion, n = 43; task‐based functional, n = 18). Statistical analyses examined whether cortical morphometry, white matter microstructure and blood oxygenation level‐dependent (BOLD) signal during an n‐back working memory task changed from pretraining to posttraining in the Cogmed and placebo groups separately. Interaction analyses between time point and group were then performed. There was a significant increase in neurite density in several white matter regions from pretraining to posttraining in both the Cogmed and placebo groups. BOLD signal in the posterior cingulate and precuneus cortices during the n‐back task increased from pretraining to posttraining in the Cogmed but not placebo group. Evidence for group‐by‐time interactions for the MRI measures was weak, suggesting that brain changes generally did not differ between Cogmed and placebo groups. Overall, while some structural and functional MRI changes between the pretraining and posttraining period in EP/ELBW children were observed, there was little evidence of training‐induced neuroplasticity, with changes generally identified in both groups. Trial registration Australian New Zealand Clinical Trials Registry, anzctr.org.au ; ACTRN12612000124831.     

Detection of high-grade cervical disease among women referred directly to colposcopy after a positive HPV screening test varies with age and cytology findings

Australia's new HPV-based cervical screening program is based on an algorithm that incorporates reflex cytology to guide decisions about further follow-up with colposcopy and, if indicated, biopsy. We reviewed results for 2300 women referred directly for colposcopy after their first positive HPV screening test, to determine the proportion that had underlying histological high-grade abnormality (HGA). Overall, HGA was detected in 24.3% of women. Among HPV16/18 positive women, 18.0% had HGA, increasing from 6.6% among women with negative cytology to 79.7% among women with high-grade squamous lesion or worse, or any glandular lesion on cytology (HSIL+; P-trend < .001). For this latter group, the proportion with HGA was higher among HPV16/18 positive women than among those positive for other oncogenic types (68.8%; P = .029). Among women with ASC-H cytology, 51.8% had HGA, with no difference between HPV groups (P = .314). In analyses by age-groups, detection of HGA was highest, at 36.4%, among women younger than 35 years, then decreased significantly to 5.9%, among women aged 65 to 74 years (P-trend < .001). The relationship of decreasing HGA detection with increasing age was strong for women with negative cytology, and those with ASC-H cytology (P-trend < .001 for each). For women with HSIL+ cytology, detection of HGA was high and stable, regardless of age (P-trend = .211). This report describes the first follow-up colposcopy findings in Australia's new HPV-based cervical screening program. The results demonstrate the additional value of reflex cytology in managing HPV positive women and suggest that further refinement of the risk-based algorithm to account for age may be warranted.     

A hybrid form of cardiac resynchronisation therapy in patients with failing systemic right ventricles

INTRODUCTION: Late systemic right ventricular (RV) dysfunction after atrial redirection surgery is common. Patients may require cardiac transplantation in early adulthood. METHODS: We undertook cardiac resynchronisation (CRT)/defibrillator therapy in two patients as a bridge to transplantation. RESULTS: Two males (aged 24, 110 kg and 26 years, 106 kg); having undergone a Mustard procedure for dextro-transposition of the great arteries at 7 and 6 months of age respectively, presented with impaired systemic RV function and New York Heart Association III symptoms. Both patients had dual chamber pacemakers in-situ for sinus bradycardia. Upgrade to CRT was performed by conserving the existing endocardial leads and placement of epicardial electrodes. One demonstrated sustained improvement over a 24 month follow-up period. CONCLUSION: A hybrid CRT strategy is feasible in patients with failing systemic RVs and pre-existent endocardial dual chamber pacemakers. Appropriate patient selection criteria and optimum lead placement, however, still needs further evaluation in this population.     

Genetics,its role in preventing the pandemic of coronary artery disease

Epidemiologists have claimed for decades that about 50% of predisposition for coronary artery disease (CAD) is genetic. Advances in technology made possible the discovery of hundreds of genetic risk variants predisposing to CAD. Multiple clinical trials have shown that cardiac events can be prevented by drugs to lower plasma low‐density lipoprotein cholesterol (LDL‐C). A major barrier to primary prevention is the lack of markers to identify those individuals at risk prior to the development of symptoms of the disease. Conventional risk factors are age‐dependent, occurring mostly in the sixth or seventh decade, which is less than desirable for early primary prevention. A polygenic risk score, derived from the number of genetic risk variants predisposing to CAD inherited by an individual, has been evaluated in over 1 million individuals. The risk for CAD is stratified into high, intermediate, and low. Polygenic risk scores derived from retrospective genotyping of several clinical trials evaluating the effect of statin therapy or PCSK9 inhibitors show the genetic risk is reduced 40%–50% by decreasing plasma LDL‐C. Prospective randomized placebo‐controlled clinical trials document a 40%–50% reduction in cardiac events in individuals at high genetic risk associated with favorable lifestyle changes and increased physical activity. The polygenic risk score is not age‐dependent and remains the same throughout life. Thus, the GRS is superior to conventional risk factors in identifying asymptomatic individuals at risk for CAD early in life for primary prevention. These results indicate clinical embracement of the GRS in primary prevention would be a paradigm shift in the treatment of the number one killer, CAD.     

High quality metaphases from solid ovarian tumors

Cytogenetic studies of human solid tumor tissue are hampered by poor quality preparations. Using a method of short-term tissue culture developed for ovarian carcinoma specimens, we have obtained large numbers of high quality metaphases suitable for analysis from 19 of 28 ovarian tumors studied.     

Auto-tumor immunity in patients with solid tumors: participation of CD3 complex and MHC class I antigens in the lytic interaction

In a number of experiments performed with blood lymphocytes of patients, the high density subset lysed autologous tumor cells separated from the surgical specimens. The lysis was abrogated by pretreatment of the effector cells with antibodies (OKT3) directed against the T3 molecule associated with the T cell receptor and by pretreatment of the target cells with antibodies (W6/32) directed against the monomorphic part of the MHC class I antigens. This subset lyses only autologous tumor cells. The selectivity and the characteristics shared with antigen specific cytotoxic T lymphocytes (CTL) suggest that the auto-tumor lysis by the effectors reflects an immune response against the tumor cells. The low density lymphocytes, separated from the blood, can lyse both auto- and allogeneic tumor cell. In the autologous system, incubation of the effectors with the mAb OKT3 had no inhibitory effect and incubation of the targets with the anti W6/32 mAb inhibited their lysis only in some experiments. The nature of the reactivity of the LD lymphocytes remains to be defined. Whether it is similar to the indiscriminative natural killing or whether part of these lymphocytes are antigen(s) specific and exhibit a high avidity interaction with the target remains to be seen. It is possible that both types of target recognition occur since the LD lymphocyte population is heterogeneous.     

Purification and properties of porcine polymorphonuclear cells

A method for the rapid separation of highly purified populations of porcine polymorphonuclear cells from whole blood is described. Porcine blood, anti-coagulated with EDTA, was layered over a discontinuous Percoll gradient (62.5% and 75%) and then centrifuged at 400 X g for 25 min. This results in the formation of a band of cells at the interface of the two Percoll layers which is greater than 99% granulocytes (93.8 +/- 1.8% neutrophils and 5.3 +/- 1.8% eosinophils) with a 77% recovery. The mononuclear cells remain above the 62.5% Percoll layer, and most erythrocytes pellet to the bottom of the tube. The isolated porcine granulocytes were found to respond to opsonized zymosan, phorbol myristate acetate (20 ng/ml), and the calcium ionophore A23187 (10(-5) M) in chemiluminescence assays with kinetics similar to those of human granulocytes. The porcine cells did not respond to the chemotactic peptide N-formyl-methionyl-leucyl-phenalanine (FMLP; 10(-6) M) unlike the human granulocytes which display a very rapid response to FMLP. Both porcine and human granulocytes readily changed shape by elongating and developing pseudopods when exposed to zymosan-activated serum, but only human granulocytes changed on exposure to FMLP. Thus, porcine granulocytes may be rapidly isolated on discontinuous Percoll gradients with little mononuclear cell contamination. Porcine and human PMN have similar oxidative and chemotactic responses, but porcine PMN differ from human granulocytes in the inability of porcine granulocytes to respond to FMLP.     

Developments in the field of allergy mechanisms in 2015 through the eyes of Clinical & Experimental Allergy

In the first of two papers we described the development in the field of allergy mechanisms as described by Clinical and Experimental Allergy in 2015. Experimental models of allergic disease, basic mechanisms, clinical mechanisms and allergens are all covered. A second paper will cover clinical aspects.     

Preparation and characterization of copper-67 porphyrin-antibody conjugates

Methods were developed to label antibodies with copper-67, a potentially useful medical radioisotope, using the porphyrin chelating agent N-benzyl-5,10,15,20-tetrakis(4-carboxyphenyl) porphine. The porphyrin was activated for coupling using either (1) 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide HCl and N-hydroxysuccinimide or (2) 1,1'-carbonyldiimidazole. The coupling reactions were optimized as a function of activation time, coupling time, coupling pH, and reagent concentrations to achieve maximum coupling to IgG monomer. Sodium dodecylsulfate polyacrylamide gel electrophoresis was used to determine coupling yields. After purification by gel filtration, the antibody-porphyrin conjugates were labeled with copper-67 in aqueous solution. The coupling protocols were used to label antibodies from several species, demonstrating the general utility of these methods. Characterization of the conjugates indicated that the porphyrin label was attached randomly to the IgG molecule. Antigen binding capacities after conjugation were unaltered or slightly lowered as determined by a competitive ELISA.