General practitioner involvement in follow-up of childhood cancer survivors: a systematic review

BACKGROUND An increasing number of childhood cancer survivors need long-term follow-up care. Different models address this problem, including that of follow-up by general practitioners (GP). We describe models that involve GPs in follow-up for childhood cancer survivors, their advantages and disadvantages, clinics that employ these models, and the elements essential to high-quality, GP-led follow-up care. PROCEDURE We searched four databases (PubMed [including Medline], Embase, Cochrane, and CINAHL) without language restrictions. RESULTS We found 26 publications, which explicitly mentioned GP-led follow-up. Two models were commonly described: GP-only, and shared care between GP and pediatric oncology or late effects clinic. The shared care model appears to have advantages over GP-only follow-up. We found four clinics using models of GP-led follow-up, described in five papers. We identified well-organized transition, treatment summary, survivorship care plan, education of GPs and guidelines as necessary components of successful follow-up. CONCLUSION Scarcity of literature necessitated a review rather than a meta-analysis. More research on the outcomes of GP-led care is necessary to confirm the model for follow-up of childhood cancer survivors in the long term. However, with the necessary elements in place, the model of GP-led follow-up, and shared care in particular, holds promise.

Predictors of health care professionals' attitudes towards involvement in safety-relevant behaviours

BACKGROUND Patients can make valuable contributions towards promoting the safety of their health care. Health care professionals (HCPs) could play an important role in encouraging patient involvement in safety-relevant behaviours. However, to date factors that determine HCPs' attitudes towards patient participation in this area remain largely unexplored. OBJECTIVE To investigate predictors of HCPs' attitudes towards patient involvement in safety-relevant behaviours. DESIGN A 22-item cross-sectional fractional factorial survey that assessed HCPs' attitudes towards patient involvement in relation to two error scenarios relating to hand hygiene and medication safety. SETTING Four hospitals in London PARTICIPANTS   Two hundred sixteen HCPs (116 doctors; 100 nurses) aged between 21 and 60 years (mean: 32): 129 female. OUTCOME MEASURES Approval of patient's behaviour, HCP response to the patient, anticipated effects on the patient-HCP relationship, support for being asked as a HCP, affective rating response to the vignettes. RESULTS HCPs elicited more favourable attitudes towards patients intervening about a medication error than about hand sanitation. Across vignettes and error scenarios, the strongest predictors of attitudes were how the patient intervened and how the HCP responded to the patient's behaviour. With regard to HCP characteristics, doctors viewed patients intervening less favourably than nurses. CONCLUSIONS HCPs perceive patients intervening about a potential error less favourably if the patient's behaviour is confrontational in nature or if the HCP responds to the patient intervening in a discouraging manner. In particular, if a HCP responds negatively to the patient (irrespective of whether an error actually occurred), this is perceived as having negative effects on the HCP-patient relationship.

Pharyngolaryngeal involvement by varicella-zoster virus

INTRODUCTION Involvement of cranial nerves V, VII, and VIII by varicella-zoster virus (VZV) is widely reported in the literature, whereas involvement of cranial nerves IX and X is rarer and therefore poorly characterized. MATERIAL AND METHODS We performed a systematic review of the literature through MEDLINE (up to January 2012). We selected cases reporting pharyngolaryngeal involvement by VZV and extracted clinical features, complementary studies, treatments, and outcome. We added three cases to the existing literature. RESULTS Of the 65 screened articles, 38 were included reporting 54 cases. The main clinical features were odynodysphagia and dysphonia reflecting underlying hemipharyngolaryngeal palsy. Vesicles were seen in 66% of the patients. Besides the involvement of cranial nerves IX and X, concomitant involvement of other cranial nerves was seen in 48% of the cases. The most concerned nerves were cranial nerves VII and VIII. Virological tests (63%) and imaging (28%) were performed, with the latter being systematically normal. Seventy-two percent of patients were treated with antiviral agents and/or corticosteroids. Twenty-six percent of patients made a full recovery while the remaining had some persistent deficits. We did not find statistically significant differences in outcomes according to age or treatments received. CONCLUSIONS Pharyngolaryngeal involvement by VZV is rare and seldom restricted to the ninth and tenth cranial nerves. It occurs mostly within the context of cranial polyneuropathy. Regardless of the treatment, full recovery is rare and long-term sequelae persist in many cases, especially with speech and swallowing impairment. Close monitoring and follow-up are therefore essential.

In vitro metabolism of testosterone in the horse liver and involvement of equine CYPs 3A89, 3A94 and 3A95

Testosterone (TES) 6-β-hydroxylation is a significant metabolic step in the biotransformation of TES in human liver microsomes and reflects cytochrome P450 (CYP) 3A4/5 specific metabolic activity. Several CYP3A enzymes have been annotated in the horse genome, but functional characterization is missing. This descriptive study investigates TES metabolism in the horse liver in vitro and the qualitative contribution of three CYP3A isoforms of the horse. Metabolism of TES was investigated by using equine hepatocyte primary cultures and liver microsomes. Chemical inhibitors were used to determine the CYPs involved in TES biotransformation in equine microsomes. Single CYPs 3A89, 3A94, and 3A95, recombinantly expressed in V79 hamster lung fibroblasts, were incubated with TES and the fluorescent metabolite 7-benzyloxy-4-trifluoromethylcoumarin (BFC). The effect of ketoconazole and troleandomycin was evaluated on single CYPs. Testosterone metabolites were analyzed by HPLC and confirmed by GC/MS. In hepatocyte primary cultures, the most abundant metabolite was androstenedione (AS), whereas in liver microsomes, 6-β-hydroxytestosterone showed the largest peak. Formation of 6-β-hydroxytestosterone and 11-β-hydroxytestosterone in liver microsomes was inhibited by ketoconazole, troleandomycin, and quercetin. Equine recombinant CYP3A95 catalyzed 11-β-hydroxylation of testosterone (TES). Metabolism of BFC was significantly inhibited by ketoconazole in CYP3A95, whereas troleandomycin affected the activities of CYP3A94 and CYP3A95. Both inhibitors had no significant effect on CYP3A89. Metabolic reactions and effects of inhibitors differed between the equine CYP3A isoforms investigated. This has to be considered in future in vitro studies.

Impairment of rat postnatal lung alveolar development by glucocorticoids: involvement of the p21CIP1 and p27KIP1 cyclin-dependent kinase inhibitors

It has been shown that glucocorticoids accelerate lung development by limiting alveolar formation resulting from a premature maturation of the alveolar septa. Based on these data, the aim of the present work was to analyze the influence of dexamethasone on cell cycle control mechanisms during postnatal lung development. Cell proliferation is regulated by a network of signaling pathways that converge to the key regulator of cell cycle machinery: the cyclin-dependent kinase (CDK) system. The activity of the various cyclin/CDK complexes can be modulated by the levels of the cyclins and their CDKs, and by expression of specific CDK inhibitors (CKIs). In the present study, newborn rats were given a 4-d treatment with dexamethasone (0.1-0.01 microg/g body weight dexamethasone sodium phosphate daily on d 1-4), or saline. Morphologically, the treatment caused a significant thinning of the septa and an acceleration of lung maturation on d 4. Study of cyclin/CDK system at d 1-36 documented a transient down-regulation of cyclin/CDK complex activities at d 4 in the dexamethasone-treated animals. Analysis of the mechanisms involved suggested a role for the CKIs p21CIP1 and p27KIP1. Indeed, we observed an increase in p21CIP1 and p27KIP1 protein levels on d 4 in the dexamethasone-treated animals. By contrast, no variations in either cyclin and CDK expression, or cyclin/CDK complex formation could be documented. We conclude that glucocorticoids may accelerate lung maturation by influencing cell cycle control mechanisms, mainly through impairment of G1 cyclin/CDK complex activation.

Representation Matters: The Impact of Descriptive Women's Representation on the Political Involvement of Women

In a cross-country comparison of 33 European countries, we tested whether a high degree of female representation attenuates the assumed negative impact of gender on political involvement. Our multilevel analyses show positive interactive effects of female representation: the degree to which the representation of women in a given country's national parliament was descriptively adequate was positively related to women's ratings of the importance of politics and self-reported political interest. With respect to political participation, the findings are mixed.

The equine DNAH3 gene: SNP discovery and exclusion of an involvement in recurrent airway obstruction (RAO) in European Warmblood horses

Recurrent airway obstruction is one of the most common airway diseases affecting mature horses. Increased bronchoalveolar mucus, neutrophil accumulation in airways, and airway obstruction are the main features of this disease. Mucociliary clearance is a key component of pulmonary defense mechanisms. Cilia are the motile part of this system and a complex linear array of dynein motors is responsible for their motility by moving along the microtubules in the axonemes of cilia and flagella. We previously detected a QTL for RAO on ECA 13 in a half-sib family of European Warmblood horses. The gene encoding DNAH3 is located in the peak of the detected QTL and encodes a dynein subunit. Therefore, we analysed this gene as a positional and functional candidate gene for RAO. In a mutation analysis of all 62 exons we detected 53 new polymorphisms including 7 non-synonymous variants. We performed an association study using 38 polymorphisms in a cohort of 422 animals. However, after correction for multiple testing we did not detect a significant association of any of these polymorphisms with RAO (P>0.05). Therefore, it seems unlikely that variants at the DNAH3 gene are responsible for the RAO QTL in European Warmblood horses.

The involvement of miRNA Dysregulation in Amyotrophic Lateral Sclerosis

ALS is a neurodegenerative disease that specifically affects upper and lower motor neurons leading to progressive paralysis and death. There is currently no effective treatment. Thus, identification of the signaling pathways and cellular mediators of ALS remains a major challenge in the search for novel therapeutic approaches. Recent studies have shown that non-coding RNAs have a significant impact on normal CNS development and onset and progression of neurological disorders. Based on this evidence we specifically test the hypothesis that misregulation of miRNA expression is a common feature in familiar ALS. Hence, we are exploiting human neuroblastoma cell lines either expressing the SOD1(G93A) mutation or depleted from Fused in Sarcoma (FUS) as tools to investigate the role of miRNAs in familiar ALS. To this end we performed a genome-wide scale miRNA expression on these cells, using whole-genome small RNA deep-sequencing followed by quantitative real time validation (qPCR). This strategy allowed us to find a group of dysregulated miRNAs, which are predicted to play a role in the motorneurons physiology and pathology. We verified our data on cDNA derived from SOD1-ALS mice models at early stage of the disease and on cDNA derived from lymphocytes from a small group of ALS patients. In the future, we plan to define the mechanisms responsible for the miRNA dysregulation, by silencing or stimulating the signal transduction pathways putatively involved in miRNA expression and regulation.

Systemic light-chain amyloidosis revealed by progressive nail involvement, diffuse alopecia and sicca syndrome: report of an unusual case with a review of the literature.

Immunoglobulin light-chain (AL) amyloidosis is a form of systemic amyloidosis in which the fibrils are derived from monoclonal light chains. We report a case of a 66-year-old woman presenting with nail changes, parchment-like hand changes, progressive alopecia and sicca syndrome. Histopathological studies of biopsy specimens of the scalp, the nail, minor labial salivary glands and abdominal skin revealed deposits of AL κ-type amyloid. Urine protein electrophoresis exhibited a weak band of κ-type light chains. Based on this striking case, we here review the characteristic nail and hair manifestations associated with systemic amyloidosis. Knowledge of these signs is important for an early diagnosis of systemic amyloidosis, identification of the underlying disease and patient management.

Characterization of choline uptake in Trypanosoma brucei and involvement of a mitochondrial carrier in resistance to choline analogs

Choline is an essential nutrient for eukaryotic cells, where it is used as precursor for the synthesis of choline-­containing phospholipids, such as phosphatidylcholine (PC). Our experiments showed – for the first time – that Trypanosoma brucei, the causative agent of human African sleeping sickness, is able to take up choline from the culture medium to use for PC synthesis, indicating that trypanosomes express a transporter for choline at the plasma membrane. Further characterization in procyclic and bloodstream forms revealed that choline uptake is saturable and can be inhibited by HC-3, a known inhibitor of choline uptake in mammalian cells. To obtain additional insights on choline uptake and metabolism, we investigated the effects of choline-analogs that were previously shown to be toxic for T. brucei parasites in culture. Interestingly, we found that all analogs tested effectively inhibited choline uptake into both bloodstream and procyclic form parasites. Subsequently, selected compounds were used to search for possible candidate genes encoding choline transporters in T. brucei, using an RNAi library in bloodstream forms. We identified a protein belonging to the mitochondrial carrier family, previously annotated as TbMCP14, as prime candidate. Down‐regulation of TbMCP14 by RNAi prevented drug-­induced loss of mitochondrial membrane potential and conferred 8­‐fold resistance of T. brucei bloodstream forms to choline analogs. Conversely, over‐expression of the carrier increased parasite susceptibility more than 13-­fold. However, subsequent experiments demonstrated that TbMCP14 was not involved in metabolism of choline. Instead, growth curves in glucose‐depleted medium using RNAi or knock‐out parasites suggested that TbMCP14 is involved in metabolism of amino acids for energy production. Together, our data demonstrate that the identified member of the mitochondrial carrier family is involved in drug uptake into the mitochondrion and has a vital function in energy production in T. brucei.

Fibrinogen association with human monocytes: evidence for constitutive expression of fibrinogen receptors and for involvement of Mac-1 (CD18, CR3) in the binding

Radiolabeled fibrinogen (Fg) specifically binds to mononuclear leukocytes (MNL) and to purified monocytes, but not to nylon-nonadherent lymphocytes. The association is rapid, Ca++-dependent and reversible. MNL containing Fg-binding monocytes had not been exposed to endotoxin (less than 4 pg/mL) during the isolation and the binding test, and Fg binding was not altered by preincubation of MNL with lipopolysaccharide. The binding of Fg was inhibited by anti-Mac-1 antibodies (OKM1). Antibodies to surface-bound Fg were able to induce luminol-dependent chemiluminescence, indicating that Fg binding sites have receptor function. Emission of a signal depended on MNL exposure to Fg, on specific, divalent antibodies, but not on the antibody Fc portion. These data show that human monocytes constitutively express specific Fg receptors and suggest that Mac-1, a member of the integrin superfamily, is involved in Fg recognition.