Disease-stabilizing treatment with all-trans retinoic acid and valproic acid in acute myeloid leukemia: serum hsp70 and hsp90 levels and serum cytokine profiles are determined by the disease, patient age, and anti-leukemic treatment

Heat shock protein (HSP) 70 and HSP90 are released by primary human acute myeloid leukemia (AML) cells during stress-induced spontaneous in vitro apoptosis. The AML cells also show constitutive release of several cytokines and the systemic serum levels of several soluble mediators are altered in patients with untreated AML. In the present study, we have investigated serum levels of HSP70/HSP90 and the serum cytokine profiles of patients with untreated AML and patients receiving AML-stabilizing palliative treatment based on all-trans retinoic acid (ATRA) plus valproic acid. Patients with untreated AML showed increased HSP90 levels and a distinct serum cytokine profile when compared with healthy controls, and low pre-therapy HSP90 levels were associated with a prolonged survival during treatment with ATRA + valproic acid + theophyllin. Hierarchical cluster analysis showed a close association between HSP70, HSP90, IL-1 receptor antagonist (IL-1ra), and hepatocyte growth factor (HGF) levels. Furthermore, disease-stabilizing therapy altered the serum-cytokine profile, but the correlations between HSP70/HSP90/IL-1ra/HGF were maintained only when ATRA + valproic acid were combined with theophyllin but not when combined with cytarabine. We conclude that both HSP levels and serum cytokine profiles are altered and may represent possible therapeutic targets or prognostic markers in human AML.     

Circulating KIT D816V mutation-positive non-mast cells in peripheral blood are characteristic of indolent systemic mastocytosis

It is presently accepted that the KIT D816V mutation is detectable in tissues with neoplastic mast cells in most patients with indolent systemic mastocytosis. In this study, neoplastic mast cells were detected in bone marrow, but not in peripheral blood, by flow cytometry in all 25 included cases of indolent systemic mastocytosis. However, the KIT D816V mutation was detected using mutation-specific qPCR in both bone marrow and peripheral blood in all 25 cases, demonstrating for the first time that the KIT D816V mutation is consistently present in non-mast cells in indolent systemic mastocytosis and that these cells are circulating in peripheral blood.     

Simple function tests for autonomic neuropathy have a higher predictive value on all-cause mortality in diabetes compared to 24-h heart rate variability

AimTo compare the long-term predictive power of heart rate variability (HRV) based on 24 h ECG recordings with a battery of simple autonomic function tests with regard to all-cause mortality in diabetic individuals.Methods240 diabetic persons were randomly selected from the diabetic population. A 24-h ECG was obtained and analysed on the Pathfinder 700. In the RR Tools Program time domain and frequency domain parameters were computed. Five function tests were conducted: Valsalva ratio, heart rate response to standing (30:15 ratio), expiration/inspiration ratio (E/I ratio), orthostatic blood pressure response (Ortho BP), and increase in diastolic blood pressure during sustained handgrip.Results178 patients agreed to participate and 136 patients who completed all 5 function tests and had an acceptable ECG recording were included in the analyses. 64 individuals (47%) died during the 15½ year follow-up. Using Cox proportional hazard analyses correcting for age and gender we found that among the HRV parameters only the power in the low frequency band (LF) had an independent predictive value on all-cause mortality (p = 0.0002). Multivariate analysis of the five function tests showed that Valsalva (p = 0.002), 30:15 ratio (p = 0.037), and handgrip (p = 0.037) were independent predictors of death. When finally the independent predictors among the function tests and the HRV parameters were assessed in the same model, no significant value could be shown for LF power (p = 0.44).ConclusionThe study indicates that simple autonomic function tests are superior to HRV based on 24-h ECG recordings in predicting all-cause mortality in the diabetic population.     

Variations in Patterns of Sexual Risk Behavior among Seattle-Area MSM Based on their HIV Status,the HIV Status of their Partner and Partner Type

We evaluated sexual risk behavior in 368 Seattle-area MSM recruited in the 2008 National HIV Behavioral Surveillance survey. We found significant concordance between participants’ self-reported HIV status and that of their sexual partners. Persons unaware of partners’ HIV status were more likely to report only oral sex. Those aware were less likely to report non-concordant unprotected anal intercourse (UAI). Participants reporting themselves HIV-positive were more likely than those self-reporting HIV-negative status to report non-concordant UAI and several other sexual risk behaviors. The level of non-concordant UAI did not materially differ by whether their partner was a main or casual partner.     

Antibiotic treatment in patients with chronic low back pain and vertebral bone edema (Modic type 1 changes): a double-blind randomized clinical controlled trial of efficacy

Purpose

Modic type 1 changes/bone edema in the vertebrae are present in 6 % of the general population and 35–40 % of the low back pain population. It is strongly associated with low back pain. The aim was to test the efficacy of antibiotic treatment in patients with chronic low back pain (>6 months) and Modic type 1 changes (bone edema).

Methods

The study was a double-blind RCT with 162 patients whose only known illness was chronic LBP of greater than 6 months duration occurring after a previous disc herniation and who also had bone edema demonstrated as Modic type 1 changes in the vertebrae adjacent to the previous herniation. Patients were randomized to either 100 days of antibiotic treatment (Bioclavid) or placebo and were blindly evaluated at baseline, end of treatment and at 1-year follow-up.

Outcome measures

Primary outcome, disease-specific disability, lumbar pain. Secondary outcome leg pain, number of hours with pain last 4 weeks, global perceived health, EQ-5D thermometer, days with sick leave, bothersomeness, constant pain, magnetic resonance image (MRI).

Results

144 of the 162 original patients were evaluated at 1-year follow-up. The two groups were similar at baseline. The antibiotic group improved highly statistically significantly on all outcome measures and improvement continued from 100 days follow-up until 1-year follow-up. At baseline, 100 days follow-up, 1-year follow-up the disease-specific disability-RMDQ changed: antibiotic 15, 11, 5.7; placebo 15, 14, 14. Leg pain: antibiotics 5.3, 3.0, 1.4; placebo 4.0, 4.3, 4.3. Lumbar pain: antibiotics 6.7, 5.0, 3.7; placebo 6.3, 6.3, 6.3. For the outcome measures, where a clinically important effect size was defined, improvements exceeded the thresholds, and a trend towards a dose–response relationship with double dose antibiotics being more efficacious.

Conclusions

The antibiotic protocol in this study was significantly more effective for this group of patients (CLBP associated with Modic I) than placebo in all the primary and secondary outcomes.     

Chance in agrammatic sentence comprehension: What does it really mean? Evidence from eye movements of German agrammatic aphasic patients

Background: In addition to the canonical subject-verb-object (SVO) word order, German also allows for non-canonical order (OVS), and the case-marking system supports thematic role interpretation. Previous eye-tracking studies (Kamide et al., 2003 Kamide, Y., Scheepers, C. and Altmann, G. M. 2003. Integration of syntactic and semantic information in predictive processing: Cross-linguistic evidence from German and English. Journal of Psycholinguistics Research, 32: 37–54. doi: 10.1023/A:1021933015362 [Google Scholar]; Knoeferle, 2007 Knoeferle, P. 2007. “Comparing the time-course of processing initially ambiguous and unambiguous German SVO/OVS sentences in depicted events”. In Eye movement research. A window on mind and brain, Edited by: van Gompel, R., Fischer, M., Murray, W. and Hill, R. 517–531. Oxford, , UK/Amsterdam: Elsevier.  [Google Scholar]) have shown that unambiguous case information in non-canonical sentences is processed incrementally. For individuals with agrammatic aphasia, comprehension of non-canonical sentences is at chance level (Burchert et al., 2003 Burchert, F., De Bleser, R. and Sonntag, K. 2003. Does morphology make the difference? Agrammatic sentence comprehension in German. Brain and Language, 87: 323–342. doi: 10.1016/S0093-934X(03)00132-9[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]). The trace deletion hypothesis (Grodzinsky 1995 Grodzinsky, Y. 1995. A restrictive theory of agrammatic comprehension. Brain and Language, 50: 27–51. doi: 10.1006/brln.1995.1039[Crossref], [PubMed], [Web of Science ®] , [Google Scholar], 2000 Grodzinsky, Y. 2000. The neurology of syntax: Language use without Broca's area. Behavioral and Brain Sciences, 23: 1–71. doi: 10.1017/S0140525X00002399[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]) claims that this is due to structural impairments in syntactic representations, which force the individual with aphasia (IWA) to apply a guessing strategy. However, recent studies investigating online sentence processing in aphasia (Caplan et al., 2007 Caplan, D., Waters, G., DeDe, G., Michaud, J. and Reddy, A. 2007. A study of syntactic processing in aphasia I: Behavioral (psycholinguistic) aspects. Brain and Language, 101: 103–150. doi: 10.1016/j.bandl.2006.06.225[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]; Dickey et al., 2007 Dickey, M. W., Choy, J. J. and Thompson, C. K. 2007. Real-time comprehension of Wh-movement in aphasia: Evidence from eyetracking while listening. Brain and Language, 100: 1–22. doi: 10.1016/j.bandl.2006.06.004[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]) found that divergences exist in IWAs' sentence-processing routines depending on whether they comprehended non-canonical sentences correctly or not, pointing rather to a processing deficit explanation.

Aims: The aim of the current study was to investigate agrammatic IWAs' online and offline sentence comprehension simultaneously in order to reveal what online sentence-processing strategies they rely on and how these differ from controls' processing routines. We further asked whether IWAs' offline chance performance for non-canonical sentences does indeed result from guessing.

Methods & Procedures: We used the visual-world paradigm and measured eye movements (as an index of online sentence processing) of controls (N?=?8) and individuals with aphasia (N?=?7) during a sentence–picture matching task. Additional offline measures were accuracy and reaction times.

Outcomes & Results: While the offline accuracy results corresponded to the pattern predicted by the TDH, IWAs' eye movements revealed systematic differences depending on the response accuracy.

Conclusions: These findings constitute evidence against attributing IWAs' chance performance for non-canonical structures to mere guessing. Instead, our results support processing deficit explanations and characterise the agrammatic parser as deterministic and inefficient: it is slowed down, affected by intermittent deficiencies in performing syntactic operations, and fails to compute reanalysis even when one is detected.     

Hippocampal involvement in retrieval of odor vs. object memories

The aim of this study was to investigate the role of the human hippocampus in episodic retrieval of odors, in comparison with episodic retrieval of visual objects. Subjects encoded a set of unique odors and objects, and retrieval was tested the next day during functional magnetic resonance imaging (fMRI). Subjects were shown the names of old (studied) and new (unstudied) odors and objects, and asked to indicate which of these stimuli had been presented the previous day. The results showed that brain activation was weaker and more restricted during retrieval of odors than during retrieval of objects, which possibly reflects a general visual dominance effect. Yet, retrieval of odors and objects yielded overlapping clusters of activation the bilateral hippocampi, and the left‐sided activation was specifically increased during successful retrieval (hits > correct rejections) in both modalities. Moreover, retrieval of odors uniquely activated olfactory cortical regions, likely to reflect cortical reinstatement of sensory details. Our fMRI study is the first to make a direct comparison between olfactory and visual episodic memory, and the results provide clear evidence for modality‐independent functions of the hippocampus. © 2012 Wiley Periodicals, Inc.     

Implications of caries diagnostic strategies for clinical management decisions

Baelum V, Hintze H, Wenzel A, Danielsen B, Nyvad B. Implications of caries diagnostic strategies for clinical management decisions. Community Dent Oral Epidemiol 2011. © 2011 John Wiley & Sons A/S Abstract – Objectives: In clinical practice, a visual–tactile caries examination is frequently supplemented by bitewing radiography. This study evaluated strategies for combining visual–tactile and radiographic caries detection methods and determined their implications for clinical management decisions in a low‐caries population. Methods: Each of four examiners independently examined preselected contacting interproximal surfaces in 53 dental students aged 20–37 years using a visual–tactile examination and bitewing radiography. The visual–tactile examination distinguished between noncavitated and cavitated lesions while the radiographic examination determined lesion depth. Direct inspection of the surfaces following tooth separation for the presence of cavitated or noncavitated lesions was the validation method. The true‐positive rate (i.e. the sensitivity) and the false‐positive rate (i.e. 1‐specificity) were calculated for each diagnostic strategy. Results: Visual–tactile examination provided a true‐positive rate of 34.2% and a false‐positive rate of 1.5% for the detection of a cavity. The combination of a visual–tactile and a radiographic examination using the lesion in dentin threshold for assuming cavitation had a true‐positive rate of 76.3% and a false‐positive rate of 8.2%. When diagnostic observations were translated into clinical management decisions using the rule that a noncavitated lesion should be treated nonoperatively and a cavitated lesion operatively, our results showed that the visual–tactile method alone was the superior strategy, resulting in most correct clinical management decisions and most correct decisions regarding the choice of treatment.