Cerebral non-oxidative carbohydrate consumption in humans driven by adrenaline

During brain activation, the decrease in the ratio between cerebral oxygen and carbohydrate uptake (6 O₂/(glucose +  ¹/₂  lactate); the oxygen–carbohydrate index, OCI) is attenuated by the non-selective β-adrenergic receptor antagonist propranolol, whereas OCI remains unaffected by the β₁-adrenergic receptor antagonist metroprolol. These observations suggest involvement of a β₂-adrenergic mechanism in non-oxidative metabolism for the brain. Therefore, we evaluated the effect of adrenaline (0.08 μg kg⁻¹ min⁻¹ i.v. for 15 min) and noradrenaline (0.5, 0.1 and 0.15 μg kg⁻¹ min⁻¹ i.v. for 20 min) on the arterial to internal jugular venous concentration differences (a-v diff) of O₂, glucose and lactate in healthy humans. Adrenaline ( n = 10) increased the arterial concentrations of O₂, glucose and lactate ( P < 0.05) and also increased the a-v diff for glucose from 0.6 ± 0.1 to 0.8 ± 0.2 m m (mean ± s.d. ; P < 0.05). The a-v diff for lactate shifted from a net cerebral release to an uptake and OCI was lowered from 5.1 ± 1.5 to 3.6 ± 0.4 ( P < 0.05) indicating an 8-fold increase in the rate of non-oxidative carbohydrate uptake during adrenaline infusion ( P < 0.01). Conversely, noradrenaline ( n = 8) did not affect the OCI despite an increase in the a-v diff for glucose ( P < 0.05). These results support that non-oxidative carbohydrate consumption for the brain is driven by a β₂-adrenergic mechanism, giving neurons an abundant provision of energy when plasma adrenaline increases.     

Genetic modification of mesenchymal stem cells for cartilage repair

Reproduction of a native, functional architecture in articular cartilage defects is a major problem in orthopaedic surgery. The elaboration of workable options to heal damaged cartilage might necessitate to involve cellular, molecular and environmental components to allow for the formation of an adequate and stable repair tissue in sites of injury. Strategies based on the transfer of candidate sequences to progenitor cells offer powerful tools to achieve this goal. The aim of this report is to provide an overview of the most recent therapeutic approaches developed in experimental orthopaedic research.     

Accuracy and reliability of peer assessment of athletic training psychomotor laboratory skills

Context:

Peer assessment is defined as students judging the level or quality of a fellow student''s understanding. No researchers have yet demonstrated the accuracy or reliability of peer assessment in athletic training education.

Objective:

To determine the accuracy and reliability of peer assessment of athletic training students'' psychomotor skills.

Design:

Cross-sectional study.

Setting:

Entry-level master''s athletic training education program.

Patients or Other Participants:

First-year (n  =  5) and second-year (n  =  8) students.

Main Outcome Measure(s):

Participants evaluated 10 videos of a peer performing 3 psychomotor skills (middle deltoid manual muscle test, Faber test, and Slocum drawer test) on 2 separate occasions using a valid assessment tool. Accuracy of each peer-assessment score was examined through percentage correct scores. We used a generalizability study to determine how reliable athletic training students were in assessing a peer performing the aforementioned skills. Decision studies using generalizability theory demonstrated how the peer-assessment scores were affected by the number of participants and number of occasions.

Results:

Participants had a high percentage of correct scores: 96.84% for the middle deltoid manual muscle test, 94.83% for the Faber test, and 97.13% for the Slocum drawer test. They were not able to reliably assess a peer performing any of the psychomotor skills on only 1 occasion. However, the ϕ increased (exceeding the 0.70 minimal standard) when 2 participants assessed the skill on 3 occasions (ϕ  =  0.79) for the Faber test, with 1 participant on 2 occasions (ϕ  =  0.76) for the Slocum drawer test, and with 3 participants on 2 occasions for the middle deltoid manual muscle test (ϕ  =  0.72).

Conclusions:

Although students did not detect all errors, they assessed their peers with an average of 96% accuracy. Having only 1 student assess a peer performing certain psychomotor skills was less reliable than having more than 1 student assess those skills on more than 1 occasion. Peer assessment of psychomotor skills could be an important part of the learning process and a tool to supplement instructor assessment.     

Contralateral white noise selectively changes left human auditory cortex activity in a lexical decision task

In a previous study, we hypothesized that the approach of presenting information-bearing stimuli to one ear and noise to the other ear may be a general strategy to determine hemispheric specialization in auditory cortex (AC). In that study, we confirmed the dominant role of the right AC in directional categorization of frequency modulations by showing that fMRI activation of right but not left AC was sharply emphasized when masking noise was presented to the contralateral ear. Here, we tested this hypothesis using a lexical decision task supposed to be mainly processed in the left hemisphere. Subjects had to distinguish between pseudowords and natural words presented monaurally to the left or right ear either with or without white noise to the other ear. According to our hypothesis, we expected a strong effect of contralateral noise on fMRI activity in left AC. For the control conditions without noise, we found that activation in both auditory cortices was stronger on contralateral than on ipsilateral word stimulation consistent with a more influential contralateral than ipsilateral auditory pathway. Additional presentation of contralateral noise did not significantly change activation in right AC, whereas it led to a significant increase of activation in left AC compared with the condition without noise. This is consistent with a left hemispheric specialization for lexical decisions. Thus our results support the hypothesis that activation by ipsilateral information-bearing stimuli is upregulated mainly in the hemisphere specialized for a given task when noise is presented to the more influential contralateral ear.     

Adhesion molecule protein signature in ovarian cancer effusions is prognostic of patient outcome

BACKGROUND:

Ovarian cancer cells in malignant effusions lack attachment to solid‐phase matrix substrata and receive survival stimuli through cell–cell and cell–soluble matrix molecule interactions. We hypothesized that adhesion‐related survival and proliferation pathway signals can inform clinical outcomes and guide targeted therapeutics.

METHODS:

Lysed cell pellets from a blinded set of benign (n = 20) and malignant (n = 51) peritoneal and pleural ovarian cancer patient effusions were applied to reverse‐phase protein arrays and examined using validated antibodies to adhesion‐associated protein endpoints. Results were subjected to hierarchical clustering for signature development. Association between specimen type, protein expression, and clinicopathologic associations were analyzed using the Mann‐Whitney U test. Survival outcomes were estimated using the Kaplan‐Meier method with log‐rank comparison.

RESULTS:

A cell adhesion protein signature obtained from unsupervised clustering distinguished malignant from benign effusions (P = 6.18E‐06). Protein subset analyses from malignant cases defined 3 cell adhesion protein clusters driven by E‐cadherin, epithelial cell adhesion molecule, and N‐cadherin, respectively. The components of the E‐ and N‐cadherin clusters correlated with clinical outcome by Kaplan‐Meier statistics. Univariate analysis indicated that FAK and phosphorylated AKT were associated with higher overall and progression‐free survival (PFS) (P = .03), and Akt, phosphorylated paxillin, and E‐ and N‐cadherin were associated with improved PFS (P ≤ .05). If 4 or 5 of the index adhesion proteins were high, PFS was improved by multivariate analysis (P ≤ .01).

CONCLUSIONS:

This hypothesis‐testing examination of tumor cell adhesion molecules and pathways yielded potential predictive biomarkers with which to triage patients to selected molecular therapeutics and may serve as a platform for biomarker‐based stratification for clinical application. Cancer 2011;. Published 2011 by the American Cancer Society.     

Lack of independent prognostic and predictive value of centromere 17 copy number changes in breast cancer patients with known HER2 and TOP2A status

The clinical benefit of anthracyclines has been connected to HER2 status, TOP2A status and centromere 17 copy numbers (CEN-17). Data from a clinical trial randomizing patients to anthracyclines was used to assess whether the number of CEN-17 in breast cancers may predict incremental responsiveness to anthracyclines besides what is obtained when used relatively to TOP2A and HER2. As cut sections of paraffin-embedded tissue are prone to truncation of nuclei, strict definition of ploidy levels is lacking. We therefore used normal breast tissue to assist define ploidy levels in cut sections. Fluorescence in situ hybridization (FISH) with centromere 17 (CEN-17) and TOP2A was performed on 120 normal breast specimens. The diploid CEN-17 copy number was reduced from the expected two signals in whole nuclei to an average of 1.68 signals per nucleus in cut sections of normal breast. Ploidy levels determined in normal breast were applied to data on 767 patients with known HER2 and TOP2A status randomized to anthracyclines in the DBCG 89D trial. CEN-17 ploidy levels were in cut sections from the 767 breast cancer patients established as: Haploid: ≤1.25 (10%), diploid: 1.26-2.09 (60%), triploid: 2.10-2.93 (21%), tetraploid: 2.94-3.77 (5%) or higher ploidy: ≥3.78 (4%). Amplification of HER2 and deletion of TOP2A were frequently observed in tumors with a high ploidy level. In univariate analyses increasing ploidy was associated with decreased disease-free survival (DFS) (P=0.0001) and overall survival (OS) (P<0.0001). However, in multivariate analysis CEN-17 was not established as an independent prognostic factor and was neither a statistically significant predictor of benefit from CEF (Cyclophosphamide/Epirubicin/5-Fluorouracil) compared to CMF (Cyclophosphamide/Methotrexate/5-Fluorouracil) (P(Interaction) 0.39 for DFS and 0.67 for OS). In conclusion, CEN-17 levels do not independently from TOP2A/CEN-17 ratio identify breast cancer patients who achieve an incremental benefit from adjuvant anthracyclines.     

NF-kappaB inhibition reveals differential mechanisms of TNF versus TRAIL-induced apoptosis upstream or at the level of caspase-8 activation independent of cIAP2

Death ligands not only activate a death program but also regulate inflammatory signalling pathways, for example, through NF-kappaB induction. Although tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TNF both activate NF-kappaB in human keratinocytes, only TRAIL potently induces apoptosis. However, when induction of NF-kappaB was inhibited with a kinase dead IKK2 mutant (IKK2-KD), TNF- but not TRAIL-induced apoptosis was dramatically enhanced. Acquired susceptibility to TNF-induced apoptosis was due to increased caspase-8 activation. To investigate the mechanism of resistance of HaCaT keratinocytes to TNF-induced apoptosis, we analyzed a panel of NF-kappaB-regulated effector molecules. Interestingly, the inhibitor of apoptosis protein (IAP) family member cIAP2, but not cIAP1, X-linked inhibitor of apoptosis, TNF receptor-associated factor (TRAF)-1, or TRAF2, was downregulated in sensitive but not in resistant HaCaT keratinocytes. Surprisingly, however, stable inducible expression of cIAP2 was not sufficient to render IKK2-KD-sensitized keratinocytes resistant to TNF, and reduction of cIAP2 alone did not increase the sensitivity of HaCaT keratinocytes to TNF. In conclusion, we demonstrate that inhibition of NF-kappaB dramatically sensitizes human keratinocytes to TNF- but not to TRAIL-induced apoptosis and that this sensitization for TNF was largely independent of cIAP2. Our data thus clearly exclude the candidates proposed to date to confer TNF apoptosis resistance and suggest the function of an unanticipated effector of NF-kappaB critical for the survival of HaCaT keratinocytes upstream or at the level of caspase-8 activation.     

The hair collar sign – a possible indication of cranial dysraphism

The presence of a circumscribed area of alopecia on the scalp raises several differential diagnostic considerations. A ring of hypertrichosis around such a lesion is called “hair collar sign” and raises suspicion of ectopic neural tissue and an underlying defect of the skull. We report two cases of male newborns with a hair collar surrounding a small localized area of scalp alopecia. In one child a cephalocele was diagnosed radiologically. In the other child an osseous defect was ruled out, and the histological examination confirmed the diagnosis of rudimentary meningocele after complete excision. The importance of this clinical sign has not been addressed in the German dermatological literature.     

Therapy of psoriasis in childhood and adolescence ‐ a German expert consensus

Psoriasis of childhood shows an annual prevalence of 0.71 % and accordingly has to be regarded as a frequent chronic inflammatory skin disorder of this age. The impact on the quality of life as well as development of the afflicted children and their parents is evident. On the other side, therapy is demanding with regard to the specific juvenile metabolism, physical development and skin penetration of topical drugs. Long‐term treatment at an early age has to be critically judged regarding the chronicity of the disease. Topical corticosteroids, alternatively dithranol may be used first‐line, followed by vitamin D derivatives. A combination with UV‐light, preferably UV‐B, has to be decided on an individual basis. Systemic treatment may be initiated in recalcitrant disease with methotrexate and cyclosporine where long‐term experience is available from juvenile rheumatology and transplantation medicine. Alternatively fumaric acid esters or retinoids are available. Rehabilitation procedures will help the children and their parents to cope with the disease and its treatment. The different treatment options are presented here as a German expert consensus, as clinical studies are hardly available and only a few therapeutics are licensed for this age. In any case the therapy has to be individually planned and decided together with the patients and their parents to gain maximal safety, comfort and success.