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author:("feromin, S")
1.  Spectrin Breakdown Products (SBDPs) as Potential Biomarkers for Neurodegenerative Diseases 
The world’s human population ages rapidly thanks to the great advance in modern medicine. While more and more body system diseases become treatable and curable, age-related neurodegenerative diseases remain poorly understood mechanistically, and are desperately in need of preventive and therapeutic interventions. Biomarker development consists of a key part of concerted effort in combating neurodegenerative diseases. In many chronic neurodegenerative conditions, neuronal damage/death occurs long before the onset of disease symptoms, and abnormal proteolysis may either play an active role or be a companying event of neuronal injury. Increased spectrin cleavage yielding elevated spectrin breakdown products (SBDPs) by calcium-sensitive proteases such as calpain and caspases has been established in conditions associated with acute neuronal damage such as traumatic brain injury (TBI). Here we review literature regarding spectrin expression and metabolism in the brain, and propose a potential use of SBDPs as biomarkers for neurodegenerative diseases such as Alzheimer’s diseases.
PMCID: PMC3661686  PMID: 23710421
Aging; Alzheimer’s disease; Apoptosis; Autophagy; Calcium; Calpain; Caspases; Membrane skeleton; Neuroplasticity; Neurodegeneration; Proteolysis
2.  Compartment elasticity measured by pressure-related ultrasound to determine patients “at risk” for compartment syndrome: an experimental in vitro study 
Decision-making in treatment of an acute compartment syndrome is based on clinical assessment, supported by invasive monitoring. Thus, evolving compartment syndrome may require repeated pressure measurements. In suspected cases of potential compartment syndromes clinical assessment alone seems to be unreliable. The objective of this study was to investigate the feasibility of a non-invasive application estimating whole compartmental elasticity by ultrasound, which may improve accuracy of diagnostics.
In an in vitro model, using an artificial container simulating dimensions of the human anterior tibial compartment, intra-compartmental pressures (p) were raised subsequently up to 80 mmHg by infusion of saline solution. The compartmental depth (mm) in the cross-section view was measured before and after manual probe compression (100 mmHg) upon the surface resulting in a linear compartmental displacement (∆d). This was repeated at rising compartmental pressures. The resulting displacements were related to the corresponding intra-compartmental pressures simulated in our model. A hypothesized relationship between pressures related compartmental displacement and the elasticity at elevated compartment pressures was investigated.
With rising compartmental pressures, a non-linear, reciprocal proportional relation between the displacement (mm) and the intra-compartmental pressure (mmHg) occurred. The Pearson coefficient showed a high correlation (r2 = −0.960). The intra-observer reliability value kappa resulted in a statistically high reliability (κ = 0.840). The inter-observer value indicated a fair reliability (κ = 0.640).
Our model reveals that a strong correlation between compartmental strain displacements assessed by ultrasound and the intra-compartmental pressure changes occurs. Further studies are required to prove whether this assessment is transferable to human muscle tissue. Determining the complete compartmental elasticity by ultrasound enhancement, this application may improve detection of early signs of potential compartment syndrome.
Electronic supplementary material
The online version of this article (doi:10.1186/s13037-014-0051-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4305259  PMID: 25621009
Compartment syndrome; Intra-compartmental pressure; Non-invasive diagnostic; Elasticity measurement; Elastography
3.  The future of blood-based biomarkers for Alzheimer’s disease 
Treatment of Alzheimer’s disease (AD) is significantly hampered by the lack of easily accessible biomarkers that can detect disease presence and predict disease risk reliably. Fluid biomarkers of AD currently provide indications of disease stage; however, they are not robust predictors of disease progression or treatment response, and most are measured in cerebrospinal fluid, which limits their applicability. With these aspects in mind, the aim of this article is to underscore the concerted efforts of the Blood-Based Biomarker Interest Group, an international working group of experts in the field. The points addressed include: (1) the major challenges in the development of blood-based biomarkers of AD, including patient heterogeneity, inclusion of the “right” control population, and the blood– brain barrier; (2) the need for a clear definition of the purpose of the individual markers (e.g., prognostic, diagnostic, or monitoring therapeutic efficacy); (3) a critical evaluation of the ongoing biomarker approaches; and (4) highlighting the need for standardization of preanalytical variables and analytical methodologies used by the field.
PMCID: PMC4128378  PMID: 23850333
4.  An anatomically comprehensive atlas of the adult human brain transcriptome 
Nature  2012;489(7416):391-399.
Neuroanatomically precise, genome-wide maps of transcript distributions are critical resources to complement genomic sequence data and to correlate functional and genetic brain architecture. Here we describe the generation and analysis of a transcriptional atlas of the adult human brain, comprising extensive histological analysis and comprehensive microarray profiling of ~900 neuroanatomically precise subdivisions in two individuals. Transcriptional regulation varies enormously by anatomical location, with different regions and their constituent cell types displaying robust molecular signatures that are highly conserved between individuals. Analysis of differential gene expression and gene co-expression relationships demonstrates that brain-wide variation strongly reflects the distributions of major cell classes such as neurons, oligodendrocytes, astrocytes and microglia. Local neighbourhood relationships between fine anatomical subdivisions are associated with discrete neuronal subtypes and genes involved with synaptic transmission. The neocortex displays a relatively homogeneous transcriptional pattern, but with distinct features associated selectively with primary sensorimotor cortices and with enriched frontal lobe expression. Notably, the spatial topography of the neocortex is strongly reflected in its molecular topography— the closer two cortical regions, the more similar their transcriptomes. This freely accessible online data resource forms a high-resolution transcriptional baseline for neurogenetic studies of normal and abnormal human brain function.
PMCID: PMC4243026  PMID: 22996553
Neuroscience; Genetics; Genomics; Databases
5.  CSF and Plasma Amyloid-β Temporal Profiles and Relationships with Neurological Status and Mortality after Severe Traumatic Brain Injury 
Scientific Reports  2014;4:6446.
The role of amyloid-β (Aβ) neuropathology and its significant changes in biofluids after traumatic brain injury (TBI) is still debated. We used ultrasensitive digital ELISA approach to assess amyloid-β1-42 (Aβ42) concentrations and time-course in cerebrospinal fluid (CSF) and in plasma of patients with severe TBI and investigated their relationship to injury characteristics, neurological status and clinical outcome. We found decreased CSF Aβ42 levels in TBI patients acutely after injury with lower levels in patients who died 6 months post-injury than in survivors. Conversely, plasma Aβ42 levels were significantly increased in TBI with lower levels in patients who survived. A trend analysis showed that both CSF and plasma Aβ42 levels strongly correlated with mortality. A positive correlation between changes in CSF Aβ42 concentrations and neurological status as assessed by Glasgow Coma Scale (GCS) was identified. Our results suggest that determination of Aβ42 may be valuable to obtain prognostic information in patients with severe TBI as well as in monitoring the response of the brain to injury.
PMCID: PMC4192636  PMID: 25300247
6.  Calpain cleavage and inactivation of the sodium calcium exchanger-3 occur downstream of Aβ in Alzheimer’s disease 
Aging Cell  2013;13(1):49-59.
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by pathological deposits of β-amyloid (Aβ) in senile plaques, intracellular neurofibrillary tangles (NFTs) comprising hyperphosphorylated aggregated tau, synaptic dysfunction and neuronal death. Substantial evidence indicates that disrupted neuronal calcium homeostasis is an early event in AD that could mediate synaptic dysfunction and neuronal toxicity. Sodium calcium exchangers (NCXs) play important roles in regulating intracellular calcium, and accumulating data suggests that reduced NCX function, following aberrant proteolytic cleavage of these exchangers, may contribute to neurodegeneration. Here, we show that elevated calpain, but not caspase-3, activity is a prominent feature of AD brain. In addition, we observe increased calpain-mediated cleavage of NCX3, but not a related family member NCX1, in AD brain relative to unaffected tissue and that from other neurodegenerative conditions. Moreover, the extent of NCX3 proteolysis correlated significantly with amounts of Aβ1–42. We also show that exposure of primary cortical neurons to oligomeric Aβ1–42 results in calpain-dependent cleavage of NCX3, and we demonstrate that loss of NCX3 function is associated with Aβ toxicity. Our findings suggest that Aβ mediates calpain cleavage of NCX3 in AD brain and therefore that reduced NCX3 activity could contribute to the sustained increases in intraneuronal calcium concentrations that are associated with synaptic and neuronal dysfunction in AD.
PMCID: PMC4326873  PMID: 23919677
Alzheimer’s disease; beta-amyloid; calcium; calpain; sodium calcium exchanger; tau
7.  BAALC expression: a suitable marker for prognostic risk stratification and detection of residual disease in cytogenetically normal acute myeloid leukemia 
Blood Cancer Journal  2014;4(1):e173-.
High brain and acute leukemia, cytoplasmic (BAALC) expression defines an important risk factor in cytogenetically normal acute myeloid leukemia (CN-AML). The prognostic value of BAALC expression in relation to other molecular prognosticators was analyzed in 326 CN-AML patients (<65 years). At diagnosis, high BAALC expression was associated with prognostically adverse mutations: FLT3 internal tandem duplication (FLT3-ITD) with an FLT3-ITD/FLT3 wild-type (wt) ratio of ⩾0.5 (P=0.001), partial tandem duplications within the MLL gene (MLL-PTD) (P=0.002), RUNX1 mutations (mut) (P<0.001) and WT1mut (P=0.001), while it was negatively associated with NPM1mut (P<0.001). However, high BAALC expression was also associated with prognostically favorable biallelic CEBPA (P=0.001). Survival analysis revealed an independent adverse prognostic impact of high BAALC expression on overall survival (OS) and event-free survival (EFS), and also on OS when eliminating the effect of allogeneic stem cell transplantation (SCT) (OSTXcens). Furthermore, we analyzed BAALC expression in 416 diagnostic and follow-up samples of 66 patients. During follow-up, BAALC expression correlated with mutational load or expression levels, respectively, of other minimal residual disease markers: FLT3-ITD (r=0.650, P<0.001), MLL-PTD (r=0.728, P<0.001), NPM1mut (r=0.599, P<0.001) and RUNX1mut (r=0.889, P<0.001). Moreover, a reduction in BAALC expression after the second cycle of induction chemotherapy was associated with improved EFS. Thus, our data underline the utility of BAALC expression as a marker for prognostic risk stratification and detection of residual disease in CN-AML.
PMCID: PMC3913940  PMID: 24413067
BAALC expression; CN-AML; prognosis; MRD
8.  Potential sources of interference on Abeta immunoassays in biological samples 
Therapeutic products that depend on the use of an in vitro diagnostic biomarker test to confirm their effectiveness are increasingly being developed. Use of biomarkers is particularly meaningful in the context of selecting the patient population where the therapeutic treatment is believed to be efficacious (patient enrichment). Currently available 'research-use-only' assays for Alzheimer's disease diagnosis all suffer from non-analyte and analyte-specific interferences. The impact of these interferences on the outcome of the assays is not well understood. The confounding factors are hampering correct value determination in biological samples and are intrinsic to the assay concept, the assay design, the presence in the sample of heterophilic antibodies and auto-antibodies, or might be the result of the therapeutic approach. This review focuses on the importance of assay interferences and considers how these might be minimized with the final aim of making the assays more acceptable as in vitro diagnostic biomarker tests for theranostic use.
PMCID: PMC3580396  PMID: 23082750
9.  Glial Neuronal Ratio: A Novel Index for Differentiating Injury Type in Patients with Severe Traumatic Brain Injury 
Journal of Neurotrauma  2012;29(6):1096-1104.
Neurobiochemical marker levels in blood after traumatic brain injury (TBI) may reflect structural changes detected by neuroimaging. This study evaluates whether correlations between neuronal (ubiquitin carboxy-terminal hydrolase-L1 [UCH-L1]) and glial (glial fibrillary acidic protein [GFAP]) biomarkers may be used as an indicator for differing intracranial pathologies after brain trauma. In 59 patients with severe TBI (Glasgow Coma Scale [GCS] score≤8) serum samples were obtained at the time of hospital admission and analyzed for UCH-L1 and GFAP. Glial neuronal ratio (GNR) was evaluated as the ratio between GFAP and UCH-L1 concentrations. A logistic regression analysis was used to identify variables associated with type of injury. GNR had a median of 0.85 and was positively correlated with age (R=0.45, p=0.003). Twenty-nine patients presented with diffuse injury and 30 with focal mass lesions as assessed by CT scan at admission and classified according to the Marshall Classification. GNR was significantly higher in the focal mass lesion group compared with the diffuse injury group (1.77 versus 0.48, respectively; p=0.003). Receiver operating characteristic curve analysis showed that GNR discriminated between types of injury (area under the curve [AUC]=0.72; p=0.003). GNR was more accurate earlier (≤12 h after injury) than later (AUC=0.80; p=0.002). Increased GNR was independently associated with type of injury, but not age, gender, GCS score, or mechanism of injury. GNR was significantly higher in patients who died, but was not an independent predictor of death. The data from the present study indicate that GNR provides valuable information about different injury pathways, which may be of diagnostic significance. In addition, GNR may help to identify different pathophysiological mechanisms following different types of brain trauma, with implications for therapeutic interventions.
PMCID: PMC3325554  PMID: 22165978
biomarkers; computed tomography; diagnostic; glial neuronal ratio; traumatic brain injury
10.  Manipulating Kv4.2 identifies a specific component of hippocampal pyramidal neuron A-current that depends upon Kv4.2 expression 
Journal of neurochemistry  2006;99(4):1207-1223.
The somatodendritic A-current, ISA, in hippocampal CA1 pyramidal neurons regulates the processing of synaptic inputs and the amplitude of back propagating action potentials into the dendritic tree, as well as the action potential firing properties at the soma. In this study, we have used RNA interference and over-expression to show that expression of the Kv4.2 gene specifically regulates the ISA component of A-current in these neurons. In dissociated hippocampal pyramidal neuron cultures, or organotypic cultured CA1 pyramidal neurons, the expression level of Kv4.2 is such that the ISA channels are maintained in the population at a peak conductance of approximately 950 pS/pF. Suppression of Kv4.2 transcripts in hippocampal pyramidal neurons using an RNA interference vector suppresses ISA current by 60% in 2 days, similar to the effect of expressing dominant-negative Kv4 channel constructs. Increasing the expression of Kv4.2 in these neurons increases the level of ISA to 170% of the normal set point without altering the biophysical properties. Our results establish a specific role for native Kv4.2 transcripts in forming and maintaining ISA current at characteristic levels in hippocampal pyramidal neurons.
PMCID: PMC3583589  PMID: 17026528
A-current; dominant–negative; hippocampal pyramidal neurons; Kv4 potassium channels; RNA interference; viral vectors
11.  Delayed two-stage breast reconstruction with implants: The authors’ recent experience 
In Poland, because breast cancer detection is delayed, patients usually undergo amputation or breast reconstruction. Surgeons believe that delayed reconstruction yields better aesthetic results compared with immediate reconstruction after mastectomy. Reconstruction is achieved by using either the patient’s own tissues or a tissue expander, which is later exchanged for a prosthesis/expandable implant. The two-stage reconstruction method (expander and prosthesis) is considered to be optimal because the implant position can be corrected. This study evaluated the aesthetic results of 54 patients who underwent the two-stage breast reconstruction method.
Presently, breast cancer detection is delayed in Poland and, thus, the only other option for patients is amputation and breast reconstruction (immediate or delayed). Reconstructive methods are based on using the patient’s own tissue (pedicled or free myocutaneous flaps) or implants (a tissue expander, which is later exchanged for a prosthesis or an expandable implant).
To evaluate the aesthetic results of a delayed two-stage breast reconstruction with the use of implants (expander and prosthesis) in patients who have previously undergone cancer-related mastectomy.
From 2006 to 2009, 54 patients (34 to 65 years of age) underwent reconstruction at least one year after their mastectomy and adjuvant chemotherapy; three women also received x-ray therapy. All women underwent a two-stage treatment with a tissue expander, which was later exchanged for a prosthesis.
Outcomes of the surgery (evaluated by the physician and the patient at least six months after all stages of reconstruction) were found to be very good in 42 patients and good in 12 patients. After amputation and x-ray therapy in two cases, a fistula developed, which necessitated implant removal.
After amputation, breast reconstruction with implants (expander and prosthesis) provides good aesthetic results. The method is mildly burdening to the patient and does not cause severe scarring. Symmetrization of the second breast is often recommended; however, the cost is not covered by the national health system. In principle, earlier x-ray therapy disqualifies the application of implants. Dividing reconstruction into two stages (expander and prosthesis) allows for possible correction of prosthesis placement.
PMCID: PMC3269328  PMID: 22942657
Breast implant; Breast reconstruction; Delayed; Prosthesis; Tissue expander; Two stage
12.  Kv4.2 potassium channels segregate to extrasynaptic domains and influence intrasynaptic NMDA receptor NR2B subunit expression 
Brain Structure & Function  2012;218(5):1115-1132.
Neurons of the intercalated cell clusters (ITCs) represent an important relay site for information flow within amygdala nuclei. These neurons receive mainly glutamatergic inputs from the basolateral amygdala at their dendritic domains and provide feed-forward inhibition to the central nucleus. Voltage-gated potassium channels type-4.2 (Kv4.2) are main players in dendritic signal processing and integration providing a key component of the A currents. In this study, the subcellular localization and distribution of the Kv4.2 was studied in ITC neurons by means of light- and electron microscopy, and compared to other types of central principal neurons. Several ultrastructural immunolocalization techniques were applied including pre-embedding techniques and, most importantly, SDS-digested freeze-fracture replica labeling. We found Kv4.2 densely expressed in somato-dendritic domains of ITC neurons where they show a differential distribution pattern as revealed by nearest neighbor analysis. Comparing ITC neurons with hippocampal pyramidal and cerebellar granule cells, a cell type- and domain-dependent organization in Kv4.2 distribution was observed. Kv4.2 subunits were localized to extrasynaptic sites where they were found to influence intrasynaptic NMDA receptor subunit expression. In samples of Kv4.2 knockout mice, the frequency of NR1-positive synapses containing the NR2B subunit was significantly increased. This indicates a strong, yet indirect effect of Kv4.2 on the synaptic content of NMDA receptor subtypes, and a likely role in synaptic plasticity at ITC neurons.
PMCID: PMC3748322  PMID: 22932868
Voltage-gated potassium channel; Immuno-electron microscopy; Freeze-fracture replica; Nearest neighbor analysis; Glutamatergic synapse
13.  Ubiquitin Carboxy-Terminal Hydrolase L1 (UCH-L1) is increased in cerebrospinal fluid and plasma of patients after epileptic seizure 
BMC Neurology  2012;12:85.
Clinical and experimental studies have demonstrated that seizures can cause molecular and cellular responses resulting in neuronal damage. At present, there are no valid tests for assessing organic damage to the brain associated with seizure. The aim of this study was to investigate cerebrospinal fluid (CSF) and plasma concentrations of Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a sensitive indicator of acute injury to brain neurons, in patients with tonic–clonic or partial secondarily generalized seizures due to various etiologies.
CSF and plasma concentrations of UCH-L1 were assessed in 52 patients within 48 hours after epileptic seizure and in 19 controls using ELISA assays.
CSF obtained within 48 hours after seizure or status epilepticus (SE) presented significantly higher levels of UCH-L1 compared to controls (p = 0.008). Plasma UCH-L1 concentrations were negatively correlated with time to sample withdrawal. An analysis conducted using only the first 12 hours post-seizure revealed significant differences between concentrations of UCH-L1 in plasma and controls (p = 0.025). CSF and plasma concentrations were strongly correlated with age in patients with seizure, but not in control patients. Plasma UCH-L1 levels were also significantly higher in patients after recurrent seizures (n = 4) than in those after one or two seizures (p = 0.013 and p = 0.024, respectively).
Our results suggest that determining levels of neuronal proteins may provide valuable information on the assessment of brain damage following seizure. These data might allow clinicians to make more accurate therapeutic decisions, to identify patients at risk of progression and, ultimately, to provide new opportunities for monitoring therapy and targeted therapeutic interventions.
PMCID: PMC3500207  PMID: 22931063
Biomarkers; UCH-L1; Epileptic seizures; Neuronal damage
15.  Age-Related Intraneuronal Elevation of αII-Spectrin Breakdown Product SBDP120 in Rodent Forebrain Accelerates in 3×Tg-AD Mice 
PLoS ONE  2012;7(6):e37599.
Spectrins line the intracellular surface of plasmalemma and play a critical role in supporting cytoskeletal stability and flexibility. Spectrins can be proteolytically degraded by calpains and caspases, yielding breakdown products (SBDPs) of various molecular sizes, with SBDP120 being largely derived from caspase-3 cleavage. SBDPs are putative biomarkers for traumatic brain injury. The levels of SBDPs also elevate in the brain during aging and perhaps in Alzheimer’s disease (AD), although the cellular basis for this change is currently unclear. Here we examined age-related SBDP120 alteration in forebrain neurons in rats and in the triple transgenic model of AD (3×Tg-AD) relative to non-transgenic controls. SBDP120 immunoreactivity (IR) was found in cortical neuronal somata in aged rats, and was prominent in the proximal dendrites of the olfactory bulb mitral cells. Western blot and densitometric analyses in wild-type mice revealed an age-related elevation of intraneuronal SBDP120 in the forebrain which was more robust in their 3×Tg-AD counterparts. The intraneuronal SBDP120 occurrence was not spatiotemporally correlated with transgenic amyloid precursor protein (APP) expression, β-amyloid plaque development, or phosphorylated tau expression over various forebrain regions or lamina. No microscopically detectable in situ activated caspase-3 was found in the nuclei of SBDP120-containing neurons. The present study demonstrates the age-dependent intraneuronal presence of an αII-spectrin cleavage fragment in mammalian forebrain which is exacerbated in a transgenic model of AD. This novel neuronal alteration indicates that impairments in membrane protein metabolism, possibly due to neuronal calcium mishandling and/or enhancement of calcium sensitive proteolysis, occur during aging and in transgenic AD mice.
PMCID: PMC3377681  PMID: 22723836
16.  Optimal compressed sensing reconstructions of fMRI using 2D deterministic and stochastic sampling geometries 
Compressive sensing can provide a promising framework for accelerating fMRI image acquisition by allowing reconstructions from a limited number of frequency-domain samples. Unfortunately, the majority of compressive sensing studies are based on stochastic sampling geometries that cannot guarantee fast acquisitions that are needed for fMRI. The purpose of this study is to provide a comprehensive optimization framework that can be used to determine the optimal 2D stochastic or deterministic sampling geometry, as well as to provide optimal reconstruction parameter values for guaranteeing image quality in the reconstructed images.
We investigate the use of frequency-space (k-space) sampling based on: (i) 2D deterministic geometries of dyadic phase encoding (DPE) and spiral low pass (SLP) geometries, and (ii) 2D stochastic geometries based on random phase encoding (RPE) and random samples on a PDF (RSP). Overall, we consider over 36 frequency-sampling geometries at different sampling rates. For each geometry, we compute optimal reconstructions of single BOLD fMRI ON & OFF images, as well as BOLD fMRI activity maps based on the difference between the ON and OFF images. We also provide an optimization framework for determining the optimal parameters and sampling geometry prior to scanning.
For each geometry, we show that reconstruction parameter optimization converged after just a few iterations. Parameter optimization led to significant image quality improvements. For activity detection, retaining only 20.3% of the samples using SLP gave a mean PSNR value of 57.58 dB. We also validated this result with the use of the Structural Similarity Index Matrix (SSIM) image quality metric. SSIM gave an excellent mean value of 0.9747 (max = 1). This indicates that excellent reconstruction results can be achieved. Median parameter values also gave excellent reconstruction results for the ON/OFF images using the SLP sampling geometry (mean SSIM > =0.93). Here, median parameter values were obtained using mean-SSIM optimization. This approach was also validated using leave-one-out.
We have found that compressive sensing parameter optimization can dramatically improve fMRI image reconstruction quality. Furthermore, 2D MRI scanning based on the SLP geometries consistently gave the best image reconstruction results. The implication of this result is that less complex sampling geometries will suffice over random sampling. We have also found that we can obtain stable parameter regions that can be used to achieve specific levels of image reconstruction quality when combined with specific k-space sampling geometries. Furthermore, median parameter values can be used to obtain excellent reconstruction results.
PMCID: PMC3807755  PMID: 22607467
Compressive sensing; MRI; fMRI; Numerical optimization
17.  Blood-based diagnostics of traumatic brain injuries 
Traumatic brain injury is a major health and socioeconomic problem that affects all societies. However, traditional approaches to the classification of clinical severity are the subject of debate and are being supplemented with structural and functional neuroimaging, as the need for biomarkers that reflect elements of the pathogenetic process is widely recognized. Basic science research and developments in the field of proteomics have greatly advanced our knowledge of the mechanisms involved in damage and have led to the discovery and rapid detection of new biomarkers that were not available previously. However, translating this research for patients' benefits remains a challenge. In this article, we summarize new developments, current knowledge and controversies, focusing on the potential role of these biomarkers as diagnostic, prognostic and monitoring tools of brain-injured patients.
PMCID: PMC3063529  PMID: 21171922
biomarkers; clinical management; diagnostics; ELISA; prognostics; proteomics; traumatic brain injury
18.  Circulating Damage Marker Profiles Support a Neuroprotective Effect of Erythropoietin in Ischemic Stroke Patients 
Molecular Medicine  2011;17(11-12):1306-1310.
The German Multicenter EPO Stroke Trial, which investigated safety and efficacy of erythropoietin (EPO) treatment in ischemic stroke, was formally declared a negative study. Exploratory subgroup analysis, however, revealed that patients not receiving thrombolysis most likely benefited from EPO during clinical recovery, a result demonstrated in the findings of the Göttingen EPO Stroke Study. The present work investigated whether the positive signal on clinical outcome in this patient subgroup was mirrored by respective poststroke biomarker profiles. All patients of the German Multicenter EPO Stroke Trial nonqualifying for thrombolysis were included if they (a) were treated per protocol and (b) had at least two of the five follow-up blood samples for circulating damage markers drawn (n = 163). The glial markers S100B and glial fibrillary acid protein (GFAP) and the neuronal marker ubiquitin C-terminal hydrolase (UCH-L1) were measured by enzyme-linked immunosorbent assay in serum on d 1, 2, 3, 4 and 7 poststroke. All biomarkers increased poststroke. Overall, EPO-treated patients had significantly lower concentrations (area under the curve) over 7 d of observation, as reflected by the composite score of all three markers (Cronbach α = 0.811) and by UCH-L1. S100B and GFAP showed a similar tendency. To conclude, serum biomarker profiles, as an outcome measure of brain damage, corroborate an advantageous effect of EPO in ischemic stroke. In particular, reduction in the neuronal damage marker UCH-L1 may reflect neuroprotection by EPO.
PMCID: PMC3321813  PMID: 21912808
19.  Fragile X mental retardation protein regulates protein expression and mRNA translation of the potassium channel Kv4.2 
A prominent characteristic of the inherited intellectual impairment disease fragile X syndrome (FXS) is neuronal hyperexcitability, resulting in a variety of symptoms, such as hyperactivity, increased sensitivity to sensory stimuli, and a high incidence of epileptic seizures. These symptoms account for a significant part of the disease pattern, but the underlying molecular mechanisms of neuronal hyperexcitability in FXS remain poorly understood. FXS is caused by loss of expression of fragile X mental retardation protein (FMRP), which regulates synaptic protein synthesis and is a key player to limit signaling pathways downstream of metabotropic glutamate receptors 1/5 (mGlu1/5). Recent findings suggest that FMRP might also directly regulate voltage-gated potassium channels. Here, we show that total and plasma membrane protein levels of Kv4.2, the major potassium channel regulating hippocampal neuronal excitability, are reduced in the brain of an FXS mouse model. Antagonizing mGlu1/5 activity with MPEP partially rescues reduced surface Kv4.2 levels in Fmr1 KO, suggesting that excess mGlu1/5 signal activity contributes to Kv4.2 dysregulation. As an additional mechanism, we show that FMRP is a positive regulator of Kv4.2 mRNA translation and protein expression and associates with Kv4.2 mRNA in vivo and in vitro. Our results suggest that absence of FMRP-mediated positive control of Kv4.2 mRNA translation, protein expression and plasma membrane levels might contribute to excess neuronal excitability in Fmr1 KO mice, and thus imply a potential mechanism underlying FXS-associated epilepsy.
PMCID: PMC3089949  PMID: 21490210
Fragile X Syndrome; FMRP; Kv4.2; potassium channels; mRNA translation
20.  The Internet as a Source of Information for Patients Prior to Rhinoplasty 
To determine the prevalence of Internet use by patients considering rhinoplasty and to identify the impact of such information on their decisions.
Prospective analysis of the impact of information received via the Internet by patients considering rhinoplasty on their decision-making prior to surgery. Eighty six patients, scheduled for post-traumatic or aesthetic rhinoplasty, received a questionnaire, consisting of 19 questions, which sought to evaluate their perception of the importance of the Internet information to them and also collected relevant demographic and sociological data.
Respondents searched online for descriptions of medical procedures, information about how to contact other patients, pre- and post-operative pictures and making contact with a doctor. Patients considering aesthetic rhinoplasty received medical information from a third party or via the Internet. Individuals requiring post-traumatic surgical treatment were usually referred by family doctor.
Patients planning nasal aesthetic surgery form their opinions after consulting friends and searching the Internet, which can act as an important medical assistance.
PMCID: PMC3173704  PMID: 21949579
Internet; Information resources; Rhinoplasty
21.  Acute changes in short-term plasticity at synapses with elevated levels of neuronal calcium sensor-1 
Nature neuroscience  2003;6(10):1031-1038.
Short-term synaptic plasticity is a defining feature of neuronal activity, but the underlying molecular mechanisms are poorly understood. Depression of synaptic activity might be due to limited vesicle availability, whereas facilitation is thought to result from elevated calcium levels. However, it is unclear whether the strength and direction (facilitation versus depression) of plasticity at a given synapse result from preexisting synaptic strength or whether they are regulated by separate mechanisms. Here we show, in rat hippocampal cell cultures, that increases in the calcium binding protein neuronal calcium sensor-1 (NCS-1) can switch paired-pulse depression to facilitation without altering basal synaptic transmission or initial neurotransmitter release probability. Facilitation persisted during high-frequency trains of stimulation, indicating that NCS-1 can recruit ‘dormant’ vesicles. Our results suggest that NCS-1 acts as a calcium sensor for short-term plasticity by facilitating neurotransmitter output independent of initial release. We conclude that separate mechanisms are responsible for determining basal synaptic strength and short-term plasticity.
PMCID: PMC3132582  PMID: 12947410
22.  Angiogenesis Markers Quantification in Breast Cancer and Their Correlation with Clinicopathological Prognostic Variables 
Pathology Oncology Research  2011;17(4):809-817.
Tumoural angiogenesis is essential for the growth and spread of breast cancer cells. Therefore the aim of this study was to assess the diagnostic performance of angiogenesis markers in tumours and there reflecting levels in serum of breast cancer patients. Angiogenin, Ang2, fibroblast growth factor basic, intercellular adhesion molecule (ICAM)-1, keratinocyte growth factor (KGF), platelet-derived growth factor-BB, and VEGF-A were measured using a FASTQuant angiogenic growth factor multiplex protein assay. We observed that breast cancer tumours exhibited high levels of PDGF-BB, bFGF and VEGF, and extremely high levels of TIMP-1 and Ang-2, whereas in serum we found significantly higher levels of Ang-2, PDGF-BB, bFGF, ICAM-1 and VEGF in patients with breast cancer compared to the benign breast diseases patients. Moreover, some of these angiogenesis markers evaluated in tumour and serum of breast cancer patients exhibited association with standard clinical parameters, ER status as well as MVD of tumours. Angiogenesis markers play important roles in tumour growth, invasion and metastasis. Our results suggest that analysis of angiogenesis markers in tumour and serum of breast cancer patients using multiplex protein assay can improve diagnosis and prognosis in this diseases.
PMCID: PMC3185224  PMID: 21560015
Breast cancer; Angiogenesis; Cancer progression; Multiplex protein assay
23.  Kv4.2 channels tagged in the S1–S2 loop for alpha-bungarotoxin binding provide a new tool for studies of channel expression and localization 
Channels (Austin, Tex.)  2010;4(2):115-123.
We report the first successful insertion of an engineered, high-affinity α-bungarotoxin (Bgtx) binding site into a voltage-gated ion channel, Kv4.2, using a short, intra-protein embedded sequence (GGWRYYESSLEPYPDGG), derived from a previously described mimotope peptide, HAP. A major benefit to this approach is the ability to live-image the distribution and fate of functional channels on the plasma membrane surface. The Bgtx binding sequence was introduced into the putative extracellular loop between the S1 and S2 transmembrane domains of Kv4.2. Following co-expression with KChIP3 in tsA201 cells, S1–S2 HAP-tagged channels express at levels comparable to wild-type Kv4.2, and their activation and inactivation kinetics are minimally altered under most conditions. Binding assays, as well as live staining of surface-expressed Kv4.2 channels with fluorescent-Bgtx, readily demonstrate specific binding of Bgtx to HAP-tagged Kv4.2 expressed on the surface of tsA201 cells. Similar live-imaging results were obtained with HAP-tagged Kv4.2 transfected into hippocampal neurons in primary culture suggesting applicability for future in vivo studies. Furthermore, the activation kinetics of S1–S2-tagged Kv4.2 channels are minimally affected by the binding of Bgtx, suggesting a limited role if any for the S1–S2 loop in voltage sensing or gating associated conformational changes. Successful functional insertion of the HAP sequence into the S1–S2 linker of Kv4.2 suggests that other related channels may similarly be amenable to this tagging strategy.
PMCID: PMC2888848  PMID: 20139708
Kv4.2; S1-S2 loop; alpha-bungarotoxin; trafficking; ion channel; mutagenesis
24.  Individual and ethnic aspects of preoperative planning for posttraumatic rhinoplasty 
The aim of this study was to compare the aesthetic results of post traumatic rhinoplasty among Europeans with populations of healthy Caucasians described in earlier reports, and to collate correct parameters of nasal shape in healthy representatives of both sexes and various races for improvement in aesthetic results of surgery. 3-D scanning of the face was performed in 54 patients after posttraumatic septorhinoplasty. Analysis of 3D model was based on two indices of the nasal proportions and four angles of the region from 18 anthropological points. Parameters of the nasal shape in addition to gender were compared to average values of healthy Caucasian population, described before. Normal characteristics of the nose among individuals of three races from previous studies were also compared to one another. In females, mean height and width of the nose as well as length of both nostrils was smaller. Neither were there any significant differences in width of the nostrils and length of the nasal pyramid nor nasal prominence. Nasal proportions were similar in both sexes. Some of the nasal angles differed in addition to gender. Posttraumatic rhinoplasty resulted in correct shape of the nose similar to the healthy Caucasian population. The aesthetic nose differ among healthy individuals of the three races analysed. While preoperative planning is important, knowledge of the normal values of parameters characterising shape in both genders is equally important as the individual differences in relation to the whole face.
PMCID: PMC3139855  PMID: 21892251
Posttraumatic; Distortion of nose; Rhinoplasty; Sexual dimorphism; Caucasian race; Preoperative planning; Aesthetic nose
25.  Lack of effects of typical and atypical antipsychotics in DARPP-32 and NCS-1 levels in PC12 cells overexpressing NCS-1 
Schizophrenia is the major psychiatry disorder, which the exact cause remains unknown. However, it is well known that dopamine-mediated neurotransmission imbalance is associated with this pathology and the main target of antipsychotics is the dopamine receptor D2. Recently, it was described alteration in levels of two dopamine signaling related proteins in schizophrenic prefrontal cortex (PFC): Neuronal Calcium Sensor-1 (NCS-1) and DARPP-32. NCS-1, which is upregulated in PFC of schizophrenics, inhibits D2 internalization. DARPP-32, which is decreased in PFC of schizophrenics, is a key downstream effector in transducing dopamine signaling. We previously demonstrated that antipsychotics do not change levels of both proteins in rat's brain. However, since NCS-1 and DARPP-32 levels are not altered in wild type rats, we treated wild type PC12 cells (PC12 WT) and PC12 cells stably overexpressing NCS-1 (PC12 Clone) with antipsychotics to investigate if NCS-1 upregulation modulates DARPP-32 expression in response to antipsychotics treatment.
We chronically treated both PC12 WT and PC12 Clone cells with typical (Haloperidol) or atypical (Clozapine and Risperidone) antipsychotics for 14 days. Using western blot technique we observed that there is no change in NCS-1 and DARPP-32 protein levels in both PC12 WT and PC12 Clone cells after typical and atypical antipsychotic treatments.
Because we observed no alteration in NCS-1 and DARPP-32 levels in both PC12 WT and Clone cells treated with typical or atypical antipsychotics, we suggest that the alteration in levels of both proteins in schizophrenic's PFC is related to psychopathology but not with antipsychotic treatment.
PMCID: PMC2912242  PMID: 20565907

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