Using learning flexibly and remembering after a delay: understanding cognitive dysfunction in adults with Down syndrome.

BACKGROUND: Episodic memory deficits are a characteristic of cognitive dysfunction in people with Down syndrome (DS). However, less is known about the processes (i.e. encoding, retention or using learned information flexibly) that underlie these deficits. METHOD: We explored these abilities by administering a relational memory and inference task to participants with DS and mental age-matched controls and testing both immediately and after a 24-h delay. RESULTS: Adults with DS learned paired associates more slowly than controls but showed good recognition at both the immediate and delayed tests. Despite memory for learned pairs, adults with DS were less able to use relational learning flexibly to make inferential judgements than controls. CONCLUSIONS: These results deepen our understanding of the cognitive profile of adults with DS, demonstrating deficits in both encoding new information, and flexibly using such information. These results have important implications for workplace training and intervention programs for people with DS.

More than a virus: a qualitative study of the social implications of hepatitis B infection in China.

BACKGROUND: China has the largest absolute number of people living with hepatitis B with up to 300,000 people estimated to die each year from hepatitis B related diseases. Despite advances in immunisation, clinical management, and health policy, there is still a lack of accessible and affordable health care for people with hepatitis B. Through in-depth interviews, this study identifies the personal, social and economic impact of living with hepatitis B and considers the role of stigma and discrimination as barriers to effective clinical management of the disease. METHODS: Semi-structured qualitative interviews were held with 41 people living with hepatitis B in five Chinese cities. Participants were recruited through clinical and non-government organisations providing services to people with hepatitis B, with most (n = 32) being under the age of 35 years. RESULTS: People living with hepatitis B experience the disease as a transformative intergenerational chronic infection with multiple personal and social impacts. These include education and employment choices, economic opportunities, and the development of intimate relationships. While regulations reducing access to employment and education for people with hepatitis B have been repealed, stigma and discrimination continue to marginalise people with hepatitis B. CONCLUSIONS: Effective public policy to reduce morbidity and mortality associated with hepatitis B needs to address the lived impact of hepatitis B on families, employment and educational choices, finances, and social marginalisation.

The influence of synovial inflammation and hyperplasia on symptomatic outcomes up to 2 years post-operatively in patients undergoing partial meniscectomy.

OBJECTIVE: Synovitis is associated with pain and other symptoms in patients with knee osteoarthritis (OA), and in patients with meniscal tears even in the absence of radiographic OA. Patients undergoing arthroscopic partial meniscectomy were followed for 2 years to determine whether synovitis predicts post-operative symptoms. DESIGN: Thirty-three patients scheduled for arthroscopy were recruited for this pilot study. Symptoms were assessed using a knee pain scale, the Lysholm score, and the short form-12 (SF-12(®)) pre-operatively and at 16 weeks, 1 year and 2 years post-operatively. Synovial inflammation and hyperplasia were graded on surgical biopsies. Linear mixed effects models were tested to determine whether inflammation or hyperplasia is associated with outcome scores over time. RESULTS: Lysholm scores and SF-12(®) physical component sub-scores were worse pre-operatively in patients with inflammation (Lysholm: 52.42 [95% confidence interval (CI) 42.37, 62.47] vs 72.38 [66.03, 78.72], P < 0.001; SF-12: 36.81 [28.26, 45.37] vs 46.23 [40.14, 52.32], P < 0.05). Up to 2-years post-operatively, patients with inflammation achieved mean scores similar to those without inflammation. As a result, the mean improvement in Lysholm scores was 13.01 [1.48-24.53] points higher than patients without inflammation, P = 0.03. 33% (4/12) of patients with inflammation still had fair to poor Lysholm scores 2 years after surgery compared to 7% (1/15, P=0.14) without inflammation. No association between hyperplasia and symptoms was noted. CONCLUSIONS: In this pilot study of patients undergoing partial meniscectomy, synovial inflammation was associated with worse pre-operative symptoms, but not with poorer outcomes in the first 2 years post-arthroscopy. Larger cohorts and longer follow-up should be pursued to confirm this relationship, and determine if the initial response is sustained.

Gemcitabine-induced thrombotic microangiopathy.

Thrombotic microangiopathy (TMA) is a microvascular occlusive disorder characterised by platelet aggregation, thrombocytopenia and end-organ damage. It is commonly idiopathic, although several drug classes, including cytotoxic chemotherapy, have been implicated. Several of cases of gemcitabine-induced TMA have been documented with incidence likely to increase with the escalating use of gemcitabine. We report the cases of two patients who developed TMA while on gemcitabine chemotherapy.

Genetic diversity of MHC class I loci in six non-model frogs is shaped by positive selection and gene duplication.

Comparative studies of major histocompatibility complex (MHC) genes across vertebrate species can reveal the evolutionary processes that shape the structure and function of immune regulatory proteins. In this study, we characterized MHC class I sequences from six frog species representing three anuran families (Hylidae, Centrolenidae and Ranidae). Using cDNA from our focal species, we amplified a total of 79 unique sequences spanning exons 2-4 that encode the extracellular domains of the functional alpha chain protein. We compared intra- and interspecific nucleotide and amino-acid divergence, tested for recombination, and identified codon sites under selection by estimating the rate of non-synonymous to synonymous substitutions with multiple codon-based maximum likelihood methods. We determined that positive (diversifying) selection was acting on specific amino-acid sites located within the domains that bind pathogen-derived peptides. We also found significant signals of recombination across the physical distance of the genes. Finally, we determined that all the six species expressed two or three putative classical class I loci, in contrast to the single locus condition of Xenopus laevis. Our results suggest that MHC evolution in anurans is a dynamic process and that variation in numbers of loci and genetic diversity can exist among taxa. Thus, the accumulation of genetic data for more species will be useful in further characterizing the relative importance of processes such as selection, recombination and gene duplication in shaping MHC loci among amphibian lineages.

Fast sequential multi element analysis of lead and cadmium in canned food samples using effervescent tablet-assisted switchable solvent based liquid phase microextraction (EA-SS-LPME) coupled with high-resolution continuum source flame atomic absorption spectrometry (HR-CS-FAAS).

An effervescent tablet-assisted switchable solvent based liquid phase microextraction (EA-SS-LPME) was developed for multi-element determination of Pb and Cd in various samples using high-resolution continuum source flame atomic absorption spectrometry (HR-CS-FAAS). The effervescent tablets were used for improving the extraction efficiency. Triethylamine as a hydrophobic solvent was switched to protonated triethylamine carbonate by CO2 and used to extract dithizone complexes from samples. Calibration linearities were obtained from 0.06 to 10.0 mg L-1 (Pb) and 0.02 to 1.50 mg L-1 (Cd). LODs of the proposed method were 0.0195 (Pb) and 0.0068 (Cd). LOQs were 0.0649 mg L-1 (Pb) and 0.0228 mg L-1 (Cd) with %RSDs of 1.25%-1.69% (Pb) and 1.07%-1.64% (Cd). The proposed method was applied for the determination of Pb and Cd in water and canned food samples. The spiked recoveries were 82.3-119.0% (Pb) and 81.7-120.0% (Cd). In addition, the PF was 3.3, with EF at 1.4 (Pb) and 2.6 (Cd) obtained after extraction for under 8 min.

Current management of adults receiving oral anti-cancer medications: A scoping review.

PURPOSE: Oral anti-cancer medication (OAM) has revolutionised oncology care. Due to their potential toxicities and associated safety challenges ongoing assessment and monitoring is essential; currently generally performed in acute care settings. Internationally there exists a transformative vision to shift patient care from acute to primary care. A nurse-led integrated model of care could be developed for OAM patient management in primary care. The aim of this study was to examine international literature regarding current clinical management practices for assessment and monitoring of patients receiving OAM. METHODS: Following PRISMA-ScR guidelines, databases MEDLINE, CINAHL and Web of Science were searched for English studies published between 2010 and 2020 using keywords: assessment, cancer, care, management, oral anticancer medications. Articles were screened and assessed for eligibility. From eligible studies, data were extracted to summarize, collate and make a narrative account of the findings. RESULTS: 2261 papers were reviewed, 14 met inclusion criteria. Three phases of management are reported: 1. Patient treatment plan development; 2. Patient education; 3. Patient monitoring. Within these phases seven specific stages of care were identified broadly representing the patient's journey: (1) treatment decision, (2) prescribing of OAM, (3) OAM dispensing and administration, (4) maximising patient safety (5) ongoing patient assessment (6) patient support (7) communication with other health-care professionals. CONCLUSIONS: Despite a paucity of international literature, a dedicated OAM clinic was endorsed as a means to achieve improved care. Nurses and pharmacists were identified as being of particular importance especially in education and ongoing management of patients receiving OAMs.

Magnetic Dispersive Solid Phase Extraction Using Recycled-graphite for GO-Fe3O4-dithizone Composite Combined with FAAS for Determination of Lead in Environmental Samples.

Magnetic dispersive solid phase extraction (MdSPE) was developed to determine the concentration of lead (Pb) in real water samples, while graphene oxide-magnetite-dithizone (GO-Fe3O4-DTZ) from the used graphite tubes (recycled graphite) of electrothermal technique was simply employed as a new sorbent to improve extraction efficiency, separated by external magnetic field and analyzed with FAAS. The synthesized sorbent was evaluated for its surface property, functional group and surface morphology by Zeta potential, Fourier transform infrared spectrophotometer (FTIR), and scanning electron microscope (SEM), respectively. The relevant measurement parameters, such as pH, extraction time, type and concentration of eluent, sample volume and reusability, were optimized. Under the optimal conditions, preconcentration factor was 13.33. The limit of detection (LOD) and limit of quantitation (LOQ) obtained were 0.070 and 0.23 mg/L, respectively. The relative standard deviation (%RSD) was 3.41%. Recovery values were 90.1 - 123%. In addition, the robustness of the method was affirmed in terms of tolerance limit obtained from interference studies.

In vivo cytotoxic T lymphocyte elicitation by mycobacterial heat shock protein 70 fusion proteins maps to a discrete domain and is CD4(+) T cell independent.

To gain insights into the mechanisms by which soluble heat shock protein (hsp) fusions can elicit CD8(+) cytotoxic T lymphocytes (CTLs) against the fusion partner, mycobacterial (Mycobacterium tuberculosis) hsp70 was dissected to ascertain whether a particular hsp domain is necessary, and knockout mice were used to determine whether the fusion protein's immunogenicity is dependent on CD4(+) T lymphocytes. We found that the ability to elicit CD8(+) CTLs depends on a discrete 200-amino acid protein domain, indicating that the fusion protein's immunogenicity for CD8(+) T cells does not require coupled chaperone function or peptide binding. Further, we found that ovalbumin (OVA).hsp70 fusion protein elicited anti-OVA CD8(+) CTLs about equally well in CD4 knockout and wild-type C57BL/6 mice, and also when the hsp70 was of murine (self) origin. The ability of hsp70 fusion proteins to elicit CD4-independent CTL responses suggests that hsp70 fusion proteins may be useful for immunological prophylaxis and therapy against disease in CD4(+) T cell-deficient individuals.

Immobilized Activated Carbon as Sorbent in Solid Phase Extraction with Cold Vapor Atomic Absorption Spectrometry for the Preconcentration and Determination of Mercury Species in Water and Freshwater Fish Samples.

A new preconcentration method using solid phase extraction (SPE) was developed by immobilizing dithizone (DZ) and 1,4-diphenylsemicarbazide (DPC) on oxidative activated carbon and then using this for the speciation and preconcentration of mercury species (Hg(II) and MeHg(I)) by flow injection cold vapor atomic absorption spectrometry (FI-CVAAS). The SPE experimental conditions were investigated including pH, amount of adsorbent and flow rate. The elution parameters and effect of foreign ions were also elucidated. Under the optimized conditions, the calibration graph was linear in the ranges of 0.015 - 3.0 µg L-1 of Hg(II), with a detection limit (LOD) of 0.0155 µg L-1, corresponding to three times the standard deviation (3SD, n = 20). The precision of the method, defined as percentage relative standard deviation (%RSD) for mercury was 1.25 - 3.79% at concentrations of 0.1 - 1.0 µg L-1, for which a preconcentration factor of 20 was obtained for Hg(II). The proposed method was validated by determining the mercury concentration in standard reference materials, and successfully applied to the speciation of mercury in several water and freshwater fish samples.

Speciation of mercury in water and freshwater fish samples by a two-step solidified floating organic drop microextraction with electrothermal atomic absorption spectrometry.

A new and simple two-step SFODME using 4-nitro-o-phenylenediamine (4-NOPD) as a chelating agent was developed for mercury speciation in water and fish samples by ETAAS. For the first step, methylmercury was extracted into 1-undecanol and for the second step, the Hg(II) remaining in the sample solution was complexed with 4-NOPD and then extracted into 1-undecanol. Under the optimized conditions, the calibration graphs of Hg(II) and methylmercury were linear in the range of 0.83-8.0 µg L-1 and 0.78-8.0 µg L-1, with the LOD of 0.25 µg L-1 and 0.24 µg L-1 and the enrichment factor were 25.7 and 32.2, respectively. The %RSDs was in the range of 2.0-4.4% at concentrations of 0.5 and 4.0 µg L-1 (n = 5). The proposed method was successfully applied to mercury speciation in water and fish samples. The accuracy of method, tested by the analysis of SRM 1566b and DORM-4 was in good agreement with the certified values.

One GABA and two acetylcholine receptors function at the C. elegans neuromuscular junction.

We describe an electrophysiological preparation of the neuromuscular junction of the nematode C. elegans, which adds to its considerable genetic and genomic resources. Mutant analysis, pharmacology and patch-clamp recording showed that the body wall muscles of wild-type animals expressed a GABA receptor and two acetylcholine receptors. The muscle GABA response was abolished in animals lacking the GABA receptor gene unc-49. One acetylcholine receptor was activated by the nematocide levamisole. This response was eliminated in mutants lacking either the unc-38 or unc-29 genes, which encode alpha and non-alpha acetylcholine receptor subunits, respectively. The second, previously undescribed, acetylcholine receptor was activated by nicotine, desensitized rapidly and was selectively blocked by dihydro-beta-erythroidine, thus explaining the residual motility of unc-38 and unc-29 mutants. By recording spontaneous endogenous currents and selectively eliminating each of these receptors, we demonstrated that all three receptor types function at neuromuscular synapses.

UNC-13 is required for synaptic vesicle fusion in C. elegans.

We analyzed the synaptic physiology of unc-13 mutants in the nematode C. elegans. Mutants of unc-13 had normal nervous system architecture, and the densities of synapses and postsynaptic receptors were normal at the neuromuscular junction. However, the number of synaptic vesicles at neuromuscular junctions was two- to threefold greater in unc-13 mutants than in wild-type animals. Most importantly, evoked release at both GABAergic and cholinergic synapses was almost absent in unc-13 null alleles, as determined by whole-cell, voltage-clamp techniques. Although mutant synapses had morphologically docked vesicles, these vesicles were not competent for release as assayed by spontaneous release in calcium-free solution or by the application of hyperosmotic saline. These experiments support models in which UNC-13 mediates either fusion of vesicles during exocytosis or priming of vesicles for fusion.

A post-docking role for active zone protein Rim.

Rim1 was previously identified as a Rab3 effector localized to the presynaptic active zone in vertebrates. Here we demonstrate that C. elegans unc-10 mutants lacking Rim are viable, but exhibit behavioral and physiological defects that are more severe than those of Rab3 mutants. Rim is localized to synaptic sites in C. elegans, but the ultrastructure of the presynaptic densities is normal in Rim mutants. Moreover, normal levels of docked synaptic vesicles were observed in mutants, suggesting that Rim is not involved in the docking process. The level of fusion competent vesicles at release sites was reduced fivefold in Rim mutants, but calcium sensitivity of release events was unchanged. Furthermore, expression of a constitutively open form of syntaxin suppressed the physiological defects of Rim mutants, suggesting Rim normally acts to regulate conformational changes in syntaxin. These data suggest Rim acts after vesicle docking likely via regulating priming.

Surfactant-assisted emulsification dispersive liquid-liquid microextraction using 2-thenoyltrifluoroacetone as a chelating agent coupled with electrothermal atomic absorption spectrometry for the speciation of chromium in water and rice samples.

A novel method was developed by SAE-DLLME for chromium speciation in water and rice samples using 2-thenoyltrifluoroacetone (TTA) as a chelating reagent by ETAAS. The speciation of Cr(III) and Cr(VI) was achieved by complexation of Cr(III)-TTA and the total Cr was measured after reduction of Cr(VI) to Cr. The calibration graph was linear in the range of 0.02-2.50 µg L-1, with a detection limit of 0.0052 µg L-1. The %RSD was in range of 2.90-3.30% at 0.5, 1.5 and 2.5 µg L-1 of Cr(III), n = 5 and the EF was 54.47. The method was applied to chromium speciation and total chromium determination in real samples and gave recoveries in the range of 96.2-103.5% and 97.1-102.7% for Cr(III) and Cr(VI) in water samples and 93.7-103.5% of total Cr in rice samples. The accuracy of the method was evaluated by analysis of SRM 1573a with good agreement compared to the certified value.

Determination of cadmium in herbs by SFODME with ETAAS detection.

A method for the determination of cadmium in herb samples based on solidified floating organic drop microextraction (SFODME) using 1-(2-Pyridylazo)-2-naphthol (PAN) as a chelating reagent and detection by electrothermal atomic absorption spectrometry (ETAAS) was developed in the present work. The effects of pH, extraction solvent, extraction time, stirring rate, and extraction temperature were investigated. Under the optimized conditions, the calibration graph was linear in the range of 0.017-3.0µgL-1, with a detection limit (LOD) of 0.0052µgL-1. The relative standard deviation (%RSD) for 6 replicate measurements of 1.0µgL-1 cadmium was ±2.67%. The method was applied to the analysis of 10 types of Thai herb samples. Percentage recoveries were in the range 94.5-110.2%. It was found that cadmium concentrations in all Thai herb samples were less than the maximum residue level.

A new species in the indigenous New Zealand soft scale insect genus Kalasiris Henderson & Hodgson (Hemiptera: Sternorrhyncha: Coccomorpha: Coccidae) on Gahnia setifolia (Cyperaceae).

The genus Kalasiris Henderson & Hodgson (Hemiptera: Sternorrhyncha: Coccomorpha: Coccidae) is currently only known from New Zealand. The adult female and pupa of a new species, K. martini Hodgson & Richmond are described and illustrated below and the possible taxonomic relationships of the genus to other New Zealand genera are discussed.

A review of new agents evaluated against pediatric acute lymphoblastic leukemia by the Pediatric Preclinical Testing Program.

Acute lymphoblastic leukemia (ALL) in children exemplifies how multi-agent chemotherapy has improved the outcome for patients. Refinements in treatment protocols and improvements in supportive care for this most common pediatric malignancy have led to a cure rate that now approaches 90%. However, certain pediatric ALL subgroups remain relatively intractable to treatment and many patients who relapse face a similarly dismal outcome. Moreover, survivors of pediatric ALL suffer the long-term sequelae of their intensive treatment throughout their lives. Therefore, the development of drugs to treat relapsed/refractory pediatric ALL, as well as those that more specifically target leukemia cells, remains a high priority. As pediatric malignancies represent a minority of the overall cancer burden, it is not surprising that they are generally underrepresented in drug development efforts. The identification of novel therapies relies largely on the reappropriation of drugs developed for adult malignancies. However, despite the large number of experimental agents available, clinical evaluation of novel drugs for pediatric ALL is hindered by limited patient numbers and the availability of effective established drugs. The Pediatric Preclinical Testing Program (PPTP) was established in 2005 to provide a mechanism by which novel therapeutics could be evaluated against xenograft and cell line models of the most common childhood malignancies, including ALL, to prioritize those with the greatest activity for clinical evaluation. In this article, we review the results of >50 novel agents and combinations tested against the PPTP ALL xenografts, highlighting comparisons between PPTP results and clinical data where possible.

IHC for Her2 with CBE356 antibody is a more accurate predictor of Her2 gene amplification by FISH than HercepTest in breast carcinoma.

BACKGROUND: Her2 (c-erbB-2/neu) overexpression in breast carcinoma predicts response to the anti-Her2 monoclonal antibody, trastuzumab, and is associated with a poor prognosis. When considering patients for trastuzumab treatment, Her2 protein expression is measured by imunohistochemistry (IHC) and, where staining is equivocal, by fluorescence in situ hybridisation (FISH) detection of Her2 gene amplification. AIMS: To compare IHC using CBE356 with IHC using the Food and Drug Administration approved HercepTesttrade mark. METHODS: CBE356 and HercepTest were analysed using 167 FISH characterised breast carcinomas. Immunohistochemical expression of Her2 was measured semiquantitatively. Sensitivity, specificity, predictive values, and overall accuracy were calculated for both IHC methods using gene amplification by FISH as the end point, and IHC and FISH assays were tested in Kaplan-Meier survival analysis. RESULTS: The accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CBE356 positive (2+ and 3+) cases were 94%, 89%, 95%, 84%, and 97%, respectively, and of HercepTest positive (2+ and 3+) cases were 91%, 66%, 98%, 92%, and 91%, respectively. A positive result with CBE356, HercepTest, or FISH was associated with significantly decreased overall survival (log rank p = 0.005, p = 0.0017, and p = 0.0005, respectively). CONCLUSIONS: Positive IHC staining for Her2 using CBE356 is 3% more accurate and 23% more sensitive at predicting Her2 gene amplification by FISH than positive staining with HercepTest. Negative IHC using CBE356 antibody is 6% more likely to represent a truly negative result than negative staining with HercepTest. Overall, CBE356 was a more accurate predictor of Her2 gene amplification by FISH than HercepTest.

Rab effector domain peptides stimulate the release of neurotransmitter from cell cultured synapses.

The involvement of the small GTP-binding protein rab3A in synaptic transmission was tested by presynaptic microinjection of guanine nucleotides and peptides corresponding to the effector domain of rab3A. When GTP gamma S injection was paired with presynaptic action potentials, the frequency of MIPSCs was increased and the evoked synaptic current was reduced in magnitude. To more specifically manipulate rab proteins, peptides were microinjected. Injection of the peptide rab3AL(33-48) or rab3(29-48) stimulated an increase in the frequency of MIPSC with little effect on action potential evoked synaptic transmission supporting a role for rab proteins in regulating synaptic transmission.