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Biomedical subjects

A D Wagner

Publications and source records attributed to A D Wagner.

At least 19 recordsLinked to original sources
PubMed2006

Gemcitabine, oxaliplatin and weekly high-dose 5-FU as 24-h infusion in chemonaive patients with advanced or metastatic pancreatic adenocarcinoma: a multicenter phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

BACKGROUND: Combinations of gemcitabine-oxaliplatin, gemcitabine-5-fluorouracil (5-FU) and 5-FU-oxaliplatin have synergistic activity and nonoverlapping adverse effect profiles. This trial assessed efficacy and safety of the triple combination gemcitabine-oxaliplatin and infusional 5-FU in patients with locally advanced (n=11) or metastatic (n=32) pancreatic adenocarcinoma. PATIENTS AND METHODS: A total of 43 eligible patients were treated with intravenous infusions of gemcitabine (900 mg/m2 over 30 min), followed by oxaliplatin (65 mg/m2 over 2 h) and 5-FU (1500 mg/m2 over 24 h) on days 1 and 8 of a 21-day cycle. RESULTS: Among all 43 patients, the tumor response rate was 19% [95% confidence interval 7% to 30%]. Nine patients were nonassessable for response because they did not complete the first two cycles of chemotherapy due to rapid disease progression, early death or treatment refusal. One patient was lost to follow-up. Median time to progression and overall survival were 5.7 and 7.5 months. Principal grade III/IV toxic effects were leucopenia in 11 (2%), thrombocytopenia in 13 (2%), nausea in 13 (0%), anorexia 16 (7%) and sensory neuropathy in 18 (0%) of patients. Unexpected cardiotoxicity was observed in this trial. CONCLUSION: Response rates and survival of the three-drug combination compare favorably with single-agent gemcitabine, but do not exceed results for doublets.

Adenocarcinoma↗
PubMed2006

[Giant cell arteritis (temporal arteritis). Pathophysiology, immunology].

The diagnosis of giant cell arteritis is established by temporal artery biopsy. The findings are those of a panarteritis with mononuclear infiltrates penetrating all layers of the arterial wall. Typically, activated T cells and macrophages are arranged in granulomas. Multinucleated giant cells, when present, are usually close to the fragmented internal elastic lamina. Often, the intimal layer is hyperplastic, leading to concentric occlusion of the lumen. The CD4(+) T cells are the main players in the disease process. T-cell activation in the arterial wall requires the presence of specialized antigen-presenting cells, the dendritic cells. The activation of monocytes and macrophages is responsible for the systemic inflammatory syndrome in giant cell arteritis and polymyalgia rheumatica. The blood vessel wall determines the site specificity of giant cell arteritis and provides the ground for the cell to cell interaction.

Antigen Presentation↗
PubMed2005

Chemotherapy for advanced gastric cancer.

BACKGROUND: Gastric cancer currently ranks second in global cancer mortality. Most patients are either diagnosed at an advanced stage, or develop a relapse after apparently curative operation. Apart from supportive measures, systemic chemotherapy is the only treatment option available in this situation. OBJECTIVES: To assess the effect of chemotherapy versus best supportive care, combination versus single agent chemotherapy and different combination chemotherapy regimens in advanced gastric cancer. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2004), MEDLINE and EMBASE up to February 2004 and reference lists of articles. We also contacted pharmaceutical companies as well as national and international experts. SELECTION CRITERIA: Randomised controlled trials on systemic intravenous chemotherapy versus best supportive care, combination versus single agent chemotherapy and different combination chemotherapies in advanced gastric cancer. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data. A third investigator was consulted in case of disagreements. We contacted study authors to obtain missing information. MAIN RESULTS: Chemotherapy versus best supportive care consistently demonstrated a significant benefit in terms of overall survival in favour of the group receiving chemotherapy (Hazard Ratios (HR) 0.39; 95% confidence intervals (CI) 0.28 to 0.52). Combination versus single-agent chemotherapy provides evidence for a survival benefit in favour of combination chemotherapy (HR 0.85; 95% CI 0.76 to 0.96). Numbers included in these comparisons were 184 and 1338 participants respectively. This benefit is achieved at the price of increased toxicity in the combination chemotherapy arms. When comparing 5-FU/cisplatin-containing combination therapy regimens with anthracyclines versus those without anthracyclines (HR 0.77; 95% CI 0.62 to 0.95 based on 501 participants) and 5-FU/anthracycline-containing combinations with cisplatin versus those without cisplatin (HR 0.83; 95% CI 0.76 to 0.91 based on 1147 participants), there was a significant survival benefit for regimens including 5-FU, anthracyclines and cisplatin. AUTHORS' CONCLUSIONS: Chemotherapy significantly improves survival in comparison to best supportive care. In addition, combination chemotherapy improves survival compared to single-agent 5-FU, but the effect size is much smaller. Among the combination chemotherapy regimens studied, best survival results are achieved with regimens containing 5-FU, anthracyclines and cisplatin. In this category, ECF (epirubicin, cisplatin and continuous infusion 5-FU) is tolerated best.

Anthracyclines↗
PubMed2005

Standardised work-up programme for fever of unknown origin and contribution of magnetic resonance imaging for the diagnosis of hidden systemic vasculitis.

BACKGROUND: Fever of unknown origin (FUO) is a diagnostic challenge. Rheumatologists are often in charge of patients with FUO because the vasculitides, especially, are potential and common causes of FUO. OBJECTIVE: To evaluate the value of a standardised investigation to identify the cause of FUO. METHODS: A standardised work-up programme for patients with FUO was started at the beginning of September 1999. The rate of identified causes of FUO was compared between all patients with FUO admitted to a tertiary care centre of rheumatology between January 1996 and August 1999 (control group) and September 1999 and January 2003 (work-up group). In January 2002 magnetic resonance imaging (MRI) was added to the investigation. RESULTS: 67 patients with FUO were identified--32 before and 35 after institution of the work-up programme. Before implementation 25% of all patients with FUO remained undiagnosed, after implementation 37%. After institution of the investigation the percentage of patients with vasculitides increased significantly from 6% (n = 2) to 26% (n = 9, p = 0.047, Fisher's exact test). This increase could be attributed to the addition of MRI in 2002. When all patients with FUO before 2002 (n = 55) and thereafter (n = 12) were compared the prevalence of systemic vasculitis increased from 11% (n = 6) to 42% (n = 5, p = 0.021). CONCLUSION: Implementation of a standardised work-up programme for FUO did not improve the overall rate of diagnosis. Addition of MRI significantly increased the diagnosis of systemic vasculitis as the underlying cause of FUO. MRI should be included in the investigation of patients with FUO when vasculitis is suspected.

Adult↗
PubMed2004

Prefrontal and hippocampal contributions to visual associative recognition: interactions between cognitive control and episodic retrieval.

The ability to recover episodic associations is thought to depend on medial-temporal lobe mnemonic mechanisms and frontal lobe cognitive control processes. The present study examined the neural circuitry underlying non-verbal associative retrieval, and considered the consequences of successful retrieval on cognitive control demands. Event-related fMRI data were acquired while subjects retrieved strongly or weakly associated pairs of novel visual patterns in a two-alternative forced choice associative recognition paradigm. Behaviorally, successful retrieval of strongly associated relative to weakly associated pairs was more likely to be accompanied by conscious recollection of the pair's prior co-occurrence. At the neural level, right ventrolateral prefrontal cortex (VLPFC) and hippocampus were more active during successful retrieval of Strong than of Weak associations, consistent with a role in visual associative recollection. By contrast, Weak trials elicited greater activation in right anterior cingulate cortex (ACC), which may detect conflict between the similarly familiar target and foil stimuli in the absence of recollection. Consistent with this interpretation, stronger ACC activity was associated with weaker hippocampal and stronger right dorsolateral PFC (DLPFC) responses. Thus, recollection of relevant visual associations (hippocampus and VLPFC) results in lower levels of mnemonic conflict (ACC) and decreased familiarity-based monitoring demands (DLPFC). These findings highlight the interplay between cognitive control and episodic retrieval.

Adult↗
PubMed2001

Cognitive neuroscience: forgetting of things past.

Recent functional imaging and electrophysiological results indicate that failure to remember experiences can result from a decreased recruitment of encoding processes that build effective memories and an increased recruitment of alternative mechanisms that may impair effective learning.

Brain↗
PubMed2001

When keeping in mind supports later bringing to mind: neural markers of phonological rehearsal predict subsequent remembering.

The ability to bring to mind a past experience depends on the cognitive and neural processes that are engaged during the experience and that support memory formation. A central and much debated question is whether the processes that underlie rote verbal rehearsal-that is, working memory mechanisms that keep information in mind-impact memory formation and subsequent remembering. The present study used event-related functional magnetic resonance imaging (fMRI) to explore the relation between working memory maintenance operations and long-term memory. Specifically, we investigated whether the magnitude of activation in neural regions supporting the on-line maintenance of verbal codes is predictive of subsequent memory for words that were rote-rehearsed during learning. Furthermore, during rote rehearsal, the extent of neural activation in regions associated with semantic retrieval was assessed to determine the role that incidental semantic elaboration may play in subsequent memory for rote-rehearsed items. Results revealed that (a) the magnitude of activation in neural regions previously associated with phonological rehearsal (left prefrontal, bilateral parietal, supplementary motor, and cerebellar regions) was correlated with subsequent memory, and (b) while rote rehearsal did not--on average--elicit activation in an anterior left prefrontal region associated with semantic retrieval, activation in this region was greater for trials that were subsequently better remembered. Contrary to the prevalent view that rote rehearsal does not impact learning, these data suggest that phonological maintenance mechanisms, in addition to semantic elaboration, support the encoding of an experience such that it can be later remembered.

Adult↗
PubMed2001

On the tip of the tongue: an event-related fMRI study of semantic retrieval failure and cognitive conflict.

The tip of the tongue (TOT) state refers to a temporary inaccessibility of information that one is sure exists in long-term memory and is on the verge of recovering. Using event-related fMRI, we assessed the neural correlates of this semantic retrieval failure to determine whether the anterior cingulate-lateral prefrontal neural circuit posited to mediate conflict resolution is engaged during metacognitive conflicts that arise during the TOT. Results revealed that, relative to successful retrieval or unsuccessful retrieval not accompanied by a TOT, retrieval failures accompanied by TOTs elicited a selective response in anterior cingulate-prefrontal cortices. During a TOT, cognitive control mechanisms may be recruited in attempts to resolve the conflict and retrieval failure that characterize this state.

Adult↗
PubMed2001

Recovering meaning: left prefrontal cortex guides controlled semantic retrieval.

Prefrontal cortex plays a central role in mnemonic control, with left inferior prefrontal cortex (LIPC) mediating control of semantic knowledge. One prominent theory posits that LIPC does not mediate semantic retrieval per se, but rather subserves the selection of task-relevant knowledge from amidst competing knowledge. The present event-related fMRI study provides evidence for an alternative hypothesis: LIPC guides controlled semantic retrieval irrespective of whether retrieval requires selection against competing representations. With selection demands held constant, LIPC activation increased with semantic retrieval demands and with the level of control required during retrieval. LIPC mediates a top-down bias signal that is recruited to the extent that the recovery of meaning demands controlled retrieval. Selection may reflect a specific instantiation of this mechanism.

Adolescent↗
PubMed2001

Can medial temporal lobe regions distinguish true from false? An event-related functional MRI study of veridical and illusory recognition memory.

To investigate the types of memory traces recovered by the medial temporal lobe (MTL), neural activity during veridical and illusory recognition was measured with the use of functional MRI (fMRI). Twelve healthy young adults watched a videotape segment in which two speakers alternatively presented lists of associated words, and then the subjects performed a recognition test including words presented in the study lists (True items), new words closely related to studied words (False items), and new unrelated words (New items). The main finding was a dissociation between two MTL regions: whereas the hippocampus was similarly activated for True and False items, suggesting the recovery of semantic information, the parahippocampal gyrus was more activated for True than for False items, suggesting the recovery of perceptual information. The study also yielded a dissociation between two prefrontal cortex (PFC) regions: whereas bilateral dorsolateral PFC was more activated for True and False items than for New items, possibly reflecting monitoring of retrieved information, left ventrolateral PFC was more activated for New than for True and False items, possibly reflecting semantic processing. Precuneus and lateral parietal regions were more activated for True and False than for New items. Orbitofrontal cortex and cerebellar regions were more activated for False than for True items. In conclusion, the results suggest that activity in anterior MTL regions does not distinguish True from False, whereas activity in posterior MTL regions does.

Behavior↗
PubMed2001

Prefrontal contributions to executive control: fMRI evidence for functional distinctions within lateral Prefrontal cortex.

The prefrontal cortex (PFC) plays a fundamental role in internally guided behavior. Although it is generally accepted that PFC subserves working memory and executive control operations, it remains unclear whether the subregions within lateral PFC support distinct executive control processes. An event-related fMRI study was implemented to test the hypothesis that ventrolateral and dorsolateral PFC are functionally distinct, as well as to assess whether functional specialization exists within ventrolateral PFC. Participants performed two executive control tasks that differed in the types of control processes required. During rote rehearsal, participants covertly rehearsed three words in the order presented, thus requiring phonological access and maintenance. During elaborative rehearsal, participants made semantic comparisons between three words held in working memory, reordering them from least to most desirable. Thus, in addition to maintenance, elaborative rehearsal required goal-relevant coding of items in working memory ("monitoring") and selection from among the items to implement their reordering. Results revealed that left posterior ventrolateral PFC was active during performance of both tasks, whereas right dorsolateral PFC was differentially engaged during elaborative rehearsal. The temporal characteristics of the hemodynamic responses further suggested that dorsolateral activation lagged ventrolateral activation. Finally, differential activation patterns were observed within left ventrolateral PFC, distinguishing between posterior and anterior regions. These data suggest that anatomically separable subregions within lateral PFC may be functionally distinct and are consistent with models that posit a hierarchical relationship between dorsolateral and ventrolateral regions such that the former monitors and selects goal-relevant representations being maintained by the latter.

Adolescent↗
PubMed2001

Perceptual specificity in visual object priming: functional magnetic resonance imaging evidence for a laterality difference in fusiform cortex.

Seeing an object on one occasion may facilitate or prime processing of the same object if it is later again encountered. Such priming may also be found -- but at a reduced level -- for different but perceptually similar objects that are alternative exemplars or 'tokens' of the initially presented object. We explored the neural correlates of this perceptual specificity using event-related functional magnetic resonance imaging (fMRI) procedures, contrasting neural activity when participants made object classification decisions (size judgments) regarding previously presented objects (repeated same), alternative exemplars of previously presented objects (repeated different), or entirely new objects (novel). Many frontal regions (including bilateral frontal operculum, bilateral posterior inferior frontal/precentral, left anterior inferior frontal, and superior frontal cortices) and multiple late visual and posterior regions (including middle occipital, fusiform, fusiform-parahippocampal, precuneus, and posterior cingulate, all bilaterally), demonstrated reduced neural activity for repeated compared to novel objects. Greater repetition-induced reductions were observed for same than for different exemplars in several of these regions (bilateral posterior inferior frontal, right precuneus, bilateral middle occipital, bilateral fusiform, bilateral parahippocampal and bilateral superior parietal). Additionally, right fusiform (occipitotemporal) cortex showed significantly less priming for different versus same exemplars than did left fusiform. These findings converge with behavioral evidence from divided visual field studies and with neuropsychological evidence underscoring the key role of right occipitotemporal cortex in processing specific visual form information; possible differences in the representational-functional role of left fusiform are discussed.

Adult↗
PubMed2001

Prefrontal regions supporting spontaneous and directed application of verbal learning strategies: evidence from PET.

The prefrontal cortex has been implicated in strategic memory processes, including the ability to use semantic organizational strategies to facilitate episodic learning. An important feature of these strategies is the way they are applied in novel or ambiguous situations-failure to initiate effective strategies spontaneously in unstructured settings is a central cognitive deficit in patients with frontal lobe disorders. The current study examined strategic memory with PET and a verbal encoding paradigm that manipulated semantic organization in three encoding conditions: spontaneous, directed and unrelated. During the spontaneous condition, subjects heard 24 words that were related in four categories but presented in mixed order, and they were not informed of this structure beforehand. Any semantic reorganization was, therefore, initiated spontaneously by the subject. In the directed condition, subjects were given a different list of 24 related words and explicitly instructed to notice relationships and mentally group related words together to improve memory. The unrelated list consisted of 24 unrelated words. Behavioural measures included semantic clustering, which assessed active regrouping of words into semantic categories during free recall. In graded PET contrasts (directed > spontaneous > unrelated), two distinct activations were found in left inferior prefrontal cortex (inferior frontal gyrus) and left dorsolateral prefrontal cortex (middle frontal gyrus), corresponding to levels of semantic clustering observed in the behavioural data. Additional covariate analyses in the first spontaneous condition indicated that blood flow in orbitofrontal cortex (OFC) was strongly correlated with semantic clustering scores during immediate free recall. Thus, blood flow in OFC during encoding predicted which subjects would spontaneously initiate effective strategies during free recall. Our findings indicate that OFC performs an important, and previously unappreciated, role in strategic memory by supporting the early mobilization of effective behavioural strategies in novel or ambiguous situations. Once initiated, lateral regions of left prefrontal cortex control verbal semantic organization.

Acoustic Stimulation↗
PubMed2000

Prefrontal-temporal circuitry for episodic encoding and subsequent memory.

Humans encounter and form memories for multiple types of experiences that differ in content, novelty, and memorability. Critical for understanding memory is determining (1) how the brain supports the encoding of events with differing content and (2) whether neural regions that are sensitive to novelty also influence whether stimuli will be subsequently remembered. This event-related functional magnetic resonance imaging (fMRI) study crossed content (picture/word), novelty (novel/repeated), and subsequent memory (remembered/forgotten) to examine prefrontal and temporal lobe contributions to encoding. Results revealed three patterns of encoding-related activation in anatomically connected inferior prefrontal and lateral temporal structures that appeared to vary depending on whether visuospatial/visuo-object, phonological/lexical, or semantic attributes were processed. Event content also modulated medial temporal lobe activity; word encoding predominantly activated the left hemisphere, whereas picture encoding activated both hemispheres. Critically, in prefrontal and temporal regions that were modulated by novelty, the magnitude of encoding activation also predicted whether an event would be subsequently remembered. These results suggest that (1) regions that demonstrate a sensitivity to novelty may actively support encoding processes that impact subsequent explicit memory and (2) multiple content-dependent prefrontal-temporal circuits support event encoding. The similarities between prefrontal and lateral temporal encoding responses raise the possibility that prefrontal modulation of posterior cortical representations is central to encoding.

Adolescent↗
PubMed2000

Detection of Chlamydia pneumoniae in giant cell vasculitis and correlation with the topographic arrangement of tissue-infiltrating dendritic cells.

OBJECTIVE: Recent studies suggest that giant cell arteritis (GCA) may be an antigen-driven disease. Since Chlamydia pneumoniae has been identified in arterial vessel walls, it was hypothesized that this organism might be associated with GCA. METHODS: Fourteen paraffin-embedded temporal artery biopsy specimens from 9 patients with GCA were examined by immunohistochemistry and by polymerase chain reaction (PCR) for the presence of C pneumoniae; for 5 patients, specimens were available from both the left and right arteries. Four temporal artery specimens from 3 patients with polymyalgia rheumatica (PMR) and 9 temporal artery specimens from 5 patients without GCA or PMR served as controls. RESULTS: C pneumoniae was detected by both immunohistochemistry and PCR in 6 GCA patient samples. One GCA patient sample was immunopositive only; another was PCR positive only. Thus, C pneumoniae was found in 8 of 9 GCA patients. One of 4 control samples from the PMR patients was immunopositive, but PCR negative, for C pneumoniae. The C pneumoniae-positive PMR patient also had respiratory symptoms. The remaining 9 control samples were negative for C pneumoniae by both immunohistochemistry and PCR. Immunohistochemistry showed that bacteria predominate in the adventitial layer of temporal arteries, in granulomatous infiltrates. Dendritic cells were examined by immunohistochemistry for their presence and localization in consecutive temporal artery specimens, and showed a strong topographic relationship with C pneumoniae. Like the bacterium, dendritic cells predominate in the adventitial layer of the arteries. CONCLUSION: C pneumoniae was found in temporal artery specimens from most GCA patients, in 1 specimen from a PMR patient, and in no other control specimens; thus, it may play a role in the pathogenesis of the disease. Dendritic cells may represent the antigen-presenting cells in this situation.

Aged↗
PubMed2000

[Azithromycin: an anti-inflammatory effect in chronic recurrent multifocal osteomyelitis? A preliminary report].

In this preliminary communication we report our experience with Azithromycin in patients with Chronic Recurring Multifocal Osteomyelitis (CRMO). Seven out of 13 patients, mainly teenager, showed a fast clinical improvement after they were started on Azithromycin. The immediate therapeutic effect of Azithromycin in patients with CRMO was surprising and lead us to the hypothesis that Azithromycin could have an antiphlogistic in addition to it's antibiotic effect in this disease setting. In patients with reactive chronic pelvic osteomyelitis Azithromycin obviously had a direct influence on the sympathic coxitis. Half of the patients reported an immediate reduction of pain and a significant improvement in range of movement after they were started on Azithromycin. In all cases the clinical and radiographic signs on MRI showed a reduction of the inflammatory process. Experimental animal models have recently shown that macrolids have independent additional antiinflammatory and immunomodulatory effects. The assumed local immunomodulatory effect of Azithromycin potentially is an additional activity to the already known synergistic antimicrobial and antiinflammatory effect. Right now we are in the process of collecting data from patients with SAPHO Syndrome who underwent bone-biopsies for microbiologic and histomorphologic investigations. All patients with the growth of propionibacterium acnes were started on a long-term antibiotic therapy with Azithromycin. This study will possibly help to answer the question of the additional antiphogistic/immunomodulatory effect of Azithromycin in this disease entity and the related CRMO.

Adolescent↗