Growth factor receptor expression in anal squamous lesions: modifications associated with oncogenic human papillomavirus and human immunodeficiency virus

High prevalence of squamous anal lesions is linked to oncogenic human papillomavirus (HPV). Human immunodeficiency virus (HIV) promotes anal carcinogenesis. Epidermal growth factor receptor (EGFR), HER2/neu, c-Met, and vascular endothelial growth factor receptor-1 (VEGFR1) (tyrosine kinase growth factor receptors) are implicated in tumor progression, but little is known about their role in anal lesions. We investigated their expression and distribution in normal, dysplastic, and carcinomatous anal epithelium and then tried to analyze the effects on these variables of HPV and the HIV-positive status. Seventy-one HIV-positive and 47 HIV-negative patients were selected. We studied growth factor receptors, p16 and Ki67 expression, by in situ hybridization, fluorescent in situ hybridization (FISH) and chromogen in situ hybridization (CISH), immunocytochemistry, and morphological quantification in 226 lesions, either infected by HPV6 and 11 (31 condylomas acuminata) or infected with oncogenic HPVs (48 invasive cancers, 147 anal intraepithelial neoplasias). No HER2/neu was detected. Strong EGFR immunolabeling was not accompanied by gene amplification. The number and intensity of EGFR- and c-Met–immunoreactive cells increased significantly during lesion progression, highlighting the effects of oncogenic HPVs. EGFR, c-Met, VEGFR1, and p16 were coexpressed in 96% of invasive cancers. HIV-modified c-Met expression in condyloma acuminata (P < .008) and invasive cancers (P < .02). Strong HIV-related immunodeficiency and an absence of antiretroviral therapy increased c-Met and/or EGFR expression. HIV-positive anal cancers showed correlated c-Met and VEGFR1 (P < .003), strong p16 labeling, and an increased Ki67 proliferation. The finding that EGFR, c-Met, and VEGFR1 involved in carcinogenesis are well-represented and coexpressed in anal cancers, especially in HIV-positive population, suggests possible novel targeted treatments for anal diseases.     

Executive function,episodic memory,and Medicare expenditures

Introduction

We examined the relationship between health care expenditures and cognition, focusing on differences across cognitive systems defined by global cognition, executive function, or episodic memory.

Psychodynamic psychotherapy of ADHD: A review of the literature

Contributions of psychodynamic psychotherapy to the treatment of children with attention deficit hyperactivity disorder (ADHD) have been sparse. However, mixed results of other interventions, including behavior therapy and medication, call for a systematic examination of psychodynamic contributions to treatment of ADHD children. A systematic review of the literature on psychodynamic psychotherapy with ADHD children yielded a combination of 23 case studies, research reports, and theoretical writings. Questions relevant to the practice of psychodynamic psychotherapy were the focus and included a review of psychodynamic diagnosis of ADHD, theoretical orientations of psychodynamic psychotherapy, identification of core treatment issues, clinical examples, and theoretical perspectives on therapeutic change as well as practice techniques. A review of 231 abstracts resulted from key word searches including ADHD, Psychotherapy, Psychodynamic, and Psychoanalytic. Once inclusion criteria were met, the information from the literature was organized according to categories reflecting the review's focus. Findings of the review are provided to guide psychodynamic psychotherapists in their treatment of ADHD children. Recommendations for future individual and group studies are discussed. (PsycINFO Database Record (c) 2012 APA, all rights reserved).     

Type II focal cortical dysplasia: electroclinical phenotype and surgical outcome related to imaging

Purpose: Type II focal cortical dysplasia (TTFCD), a highly epileptogenic lesion with severe epilepsy curable by surgery, is missed by magnetic resonance imaging (MRI) in about one third of cases. Little is known about the electroclinical presentation in these MRI‐negative patients and a poor surgical outcome is frequently reported. We compared the clinical and neurophysiologic features in MRI‐negative and MRI‐positive cases in order to better identify candidates for surgery. Methods: Among 62 consecutive TTFCD patients (38 male, 24 female; 7–52 years old; 22 children) operated for intractable epilepsy, 25 (40%) presented negative MRI findings. We compared the history of epilepsy; the type, frequency, and distribution of seizures; neurologic examination cognitive and psychiatric impairment; interictal‐ictal electroencephalography (EEG) and stereo‐EEG (SEEG) data, fluorodeoxyglucose positron emission tomography (FDG‐PET) data, neuropathologic findings; and surgical outcome in the MRI‐negative and the MRI‐positive groups. Key Findings: Severe partial epilepsy beginning in childhood, high seizure frequency including status epilepticus, stereotyped seizures suggestive of precise brain localization, extratemporal location and functional area involvement were characteristic and similarly found in both groups. On EEG, pseudorhythmic activity was found in about 40% of patients in each group. SEEG recordings demonstrated the typical pattern characterizing TTFCD in both groups. FDG‐PET had a localization value in 84% of the MRI‐negative cases and helped to delineate the dysplastic cortex in 65% of the MRI‐positive cases. The combination of imaging and neurophysiologic data allowed us to perform safe and restricted resections, limited to a single gyrus in more than half of all cases. In addition, we were able to avoid invasive monitoring in most MRI‐positive cases and even in some selected MRI‐negative cases. The proportion of patients with a favorable surgical outcome was comparable in both groups (88% in MRI‐negative and 94% in MRI‐positive cases). The main difference between the groups was a significantly higher frequency of sleep‐related epilepsy in the MRI‐negative group (p = 0.028). This phenotypic characteristic provides a new argument for TTFCD in MRI‐negative extratemporal epilepsy. Significance: These results lead us to consider that children or adult patients in whom electroclinical data suggest TTFCD, are highly suitable for surgery, especially for cryptogenic sleep‐related epilepsy.     

Experimental Evidence that In Vivo Intracerebral Administration of L-2-Hydroxyglutaric Acid to Neonatal Rats Provokes Disruption of Redox Status and Histopathological Abnormalities in the Brain

Tissue accumulation of L-2-hydroxyglutaric acid (L-2-HG) is the biochemical hallmark of L-2-hydroxyglutaric aciduria (L-2-HGA), a rare neurometabolic inherited disease characterized by neurological symptoms and brain white matter abnormalities whose pathogenesis is not yet well established. L-2-HG was intracerebrally administered to rat pups at postnatal day 1 (P1) to induce a rise of L-2-HG levels in the central nervous system (CNS). Thereafter, we investigated whether L-2-HG in vivo administration could disturb redox homeostasis and induce brain histopathological alterations in the cerebral cortex and striatum of neonatal rats. L-2-HG markedly induced the generation of reactive oxygen species (increase of 2′,7′-dichloroflurescein-DCFH-oxidation), lipid peroxidation (increase of malondialdehyde concentrations), and protein oxidation (increase of carbonyl formation and decrease of sulfhydryl content), besides decreasing the antioxidant defenses (reduced glutathione-GSH) and sulfhydryl content in the cerebral cortex. Alterations of the activities of various antioxidant enzymes were also observed in the cerebral cortex and striatum following L-2-HG administration. Furthermore, L-2-HG-induced lipid peroxidation and GSH decrease in the cerebral cortex were prevented by the antioxidant melatonin and by the classical antagonist of NMDA glutamate receptor MK-801, suggesting the involvement of reactive species and of overstimulation of NMDA receptor in these effects. Finally, L-2-HG provoked significant vacuolation and edema particularly in the cerebral cortex with less intense alterations in the striatum that were possibly associated with the unbalanced redox homeostasis caused by this metabolite. Taken together, it is presumed that these pathomechanisms may underlie the neurological symptoms and brain abnormalities observed in the affected patients.     

Effect of the branched-chain alpha-keto acids accumulating in maple syrup urine disease on S100B release from glial cells

Accumulation of the branched-chain alpha-keto acids (BCKA), alpha-ketoisocaproic acid (KIC), alpha-keto-beta-methylvaleric acid (KMV) and alpha-ketoisovaleric acid (KIV) and their respective branched-chain alpha-amino acids (BCAA) occurs in tissues and biological fluids of patients affected by the neurometabolic disorder maple syrup urine disease (MSUD). The objective of this study was to verify the effect of the BCKA on S100B release from C6 glioma cells. The cells were exposed to 1, 5 or 10 mM BCKA for different periods and the S100B release was measured afterwards. The results indicated that KIC and KIV, but not KMV, significantly enhanced S100B liberation after 6 h of exposure. Furthermore, the stimulatory effect of the BCKA on S100B release was prevented by coincubation with the energetic substrate creatine and with the N-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor, indicating that energy deficit and nitric oxide (NO) were probably involved in this effect. Furthermore, the increase of S100B release was prevented by preincubation with the protein kinase inhibitors KN-93 and H-89, indicating that KIC and KIV altered Ca2+/calmodulin (PKCaMII)- and cAMP (PKA)-dependent protein kinases activities, respectively. In contrast, other antioxidants such as glutathione (GSH) and trolox (soluble vitamin E) were not able to prevent KIC- and KIV-induced increase of S100B liberation, suggesting that the alteration of S100B release caused by the BCKA is not mediated by oxidation of sulfydryl or other essential groups of the enzyme as well as by lipid peroxyl radicals. Considering the importance of S100B for brain regulation, it is conceivable that enhanced liberation of this protein by increased levels of BCKA may contribute to the neurodegeneration characteristic of MSUD patients.     

Effects of syntactic and semantic argument structure on sentence repetition in agrammatism: Things we can learn from particles and prepositions

Background: Sentence production impairment in aphasia has been attributed to several possible sources that are not mutually exclusive. Linguistic accounts often attribute the difficulty to the complexity of a verb's syntactic and/or semantic argument structure. Cognitive processing accounts emphasise the reduced processing capacity observed in agrammatic aphasia, which in turn has been attributed to reduced semantic short-term memory (STM) or slowed processing.

Aims: In this study we used verb particles and prepositions to investigate effects of differences in syntactic and semantic argument structure on sentence repetition in aphasia. We predicted that verb particles and sentences containing verb-particle constructions would be easier to repeat than prepositions and prepositional transitive sentences, as the former have a less-complex semantic and syntactic argument structure than the latter. Also, semantic and phonological spans were assessed to determine if a reduction in either capacity correlates with repetition ability.

Methods & Procedures: Participants were eight individuals with chronic aphasia. The experimental task was repetition of transitive sentences balanced for length and lexical content containing either verb particles or prepositional object structures. Accuracy of sentence repetition and repetition of verb particles and prepositions within sentences was examined. We calculated the effect of structural complexity on the sentence repetition task as the difference between proportion correct of verb-particle constructions and prepositional transitives. Semantic and phonological STM spans and word spans were also assessed and correlated with this measure of the structural complexity effect on sentence repetition.

Outcomes & Results: Verb-particle sentences were repeated correctly significantly more often than prepositional transitive sentences, and within those sentences verbal particles were repeated correctly significantly more often than prepositions. The effect was strongly associated with fluency scores: it was present in participants with low fluency scores, but not in those with high fluency scores. The phonological, but not the semantic, STM probe span measure correlated with both the difference in accurate repetition of verb-particle and prepositional transitive sentences and the particles and prepositions within those sentences.

Conclusions: Results indicate that differences in argument structure of particle and preposition constructions influence sentence repetition in agrammatic aphasia. The finding that lower fluency scores are associated with poorer performance on more complex structures suggests that this effect is associated with agrammatism. The impact of these structural distinctions between particles and prepositions should be taken into account during development of treatment stimuli for those with agrammatism.     

Identification of a novel brain-specific and Reelin-regulated gene that encodes a protein colocalized with synapsin

We carried out a screening of genes that are differentially expressed in normal mice and reeler mutants and are characterized by abnormal neuronal migration and neurite deployment due to defective Reelin signalling. A novel gene, provisionally named C61, was overexpressed in Reelin-deficient embryonic mouse brain RNA. C61 encodes a 3.7 kb mRNA that is brain specific and developmentally regulated, with predominant expression in differentiating neurons. The predicted protein is 664 amino acids long, and contains LAG1 and Ezrin/Radixin/Moesin-Myosin-Filament motifs, suggesting that it may function as an intracellular adaptor. From E14.5 to birth, C61 was highly expressed in all neuronal differentiation fields, with the highest signal in the telencephalic cortical plate and mitral cells in the olfactory bulb. When expressed as a GFP fusion protein in transfected non-neuronal cells and primary neurons, this protein localizes, respectively, to the nuclear membrane or axonal outgrowths, indicating a function in axonal traffic or signalling.     

Training mobility tasks after stroke with combined mental and physical practice: a feasibility study

This study examines the potential of using mental practice (MP) to promote the learning of 2 mobility tasks in persons with stroke. Twelve patients were trained with MP to increase the loading of the affected limb while standing up from a chair and sitting down. Vertical forces were recorded using force plates under each foot and the chair. Changes in the loading of the affected limb and in task duration, immediately after 1 training session and 24 h later, served as outcomes. After training, the loading of the affected limb had increased (P < 0.001) during standing up (16.2%) and sitting down (17.9%), and the improvement remained significant 24 h later, indicating a learning effect. In contrast, the duration of the performance did not change with training. The results indicate that, in the early stage of learning with MP, changes in limb-loading strategies are a more sensitive measure of performance than is speed.     

Retaining older nurses in primary care and the community

Title.  Retaining older nurses in primary care and the community.
Aim.  This paper is a report of a study conducted to examine issues associated with the impact of age on the retention of female primary and community care nurses in the National Health Service in England.
Background.  Little is known about why older nurses in the primary and community care workforce leave and what might encourage them to stay.
Methods.  A cross-sectional survey using a semi-structured postal questionnaire was carried out during 2005. Responses were received from 485 (61%) district nurses, health visitors, school nurses and practice nurses in five primary care trusts in England. Data were analysed to test for associations.
Results.  Older nurses were more likely than younger ones to report that their role had lived up to expectations ( P  = 0·001). Issues important for older nurses were feeling valued and being consulted when change was implemented. Important factors encouraging nurses to stay were pension considerations, reduced working hours near retirement, and reduced workload. For those with degree-level qualifications, enhanced pay was a factor encouraging retention ( P  = 0·044). Nurses might leave in response to high administrative workloads, problems in combining work and family commitments ( P ≤  0·001), and lack of workplace support ( P  = 0·029). Retirement and pensions advice was not widely available.
Conclusion.  Since two-thirds of nurses were generally happy in their role, it is important that the conditions necessary to maintain this level of satisfaction are continued throughout a nurse's working life. Nurses may all too easily consider leaving prematurely unless policy makers and managers ensure that their working environment reflects the issues nurses consider to be conducive to retention.