[Tonometry and pachymetry to evaluate fluctuations of intraocular pressure in the context of SCUBA diving]. / Tonometrie und Pachymetrie zur Erfassung der Augeninnendruckschwankungen beim Scuba-Tauchen.

BACKGROUND: It is currently still not clarified whether diving using a self-contained breathing apparatus (SCUBA) is associated with intraocular pressure (IOP) fluctuations of clinical relevance and whether intensive diving could exacerbate the damage in glaucoma patients. OBJECTIVE: This study aimed to evaluate the effect of SCUBA diving on IOP in healthy volunteers without prior eye injuries or surgery. HYPOTHESIS: recreational diving does not lead to significant increases or fluctuations of the IOP. MATERIAL AND METHODS: The study included 16 divers (5 female) who performed a total of 96 dives with air or nitrox32 to a depth of 20-30 m for an average of 50 min. The central cornea thickness was measured using ultrasonic pachymetry Pocket IITM (Quantel Medical Pocket II™, Quantel Medical, Clermont-Ferrand, France), and the IOP was measured using an Icare® PRO (Icare® PRO, Icare Finland Oy, Espoo, Finland) directly before the dive and 10 min after surfacing. RESULTS: All data refer to the right eye. Average IOP values ranged from 15.6 to 19.2 mm Hg pre-dive and 16.8 to 18.2 mm Hg post-dive. The range of IOP values was 2.2-11.5 mm Hg pre-dive (∆ = 9.3 mm Hg) and 2.7-14.8 mm Hg post-dive (∆ = 12.1 mm Hg). Of the divers 11.5% vs. 18.8% had increased IOP values > 21 mm Hg (pre-dive vs. post-dive). CONCLUSION: This study found no significant differences in IOP values between pre-dive and post-dive measurements in healthy SCUBA divers. Therefore, recreational SCUBA diving is unlikely to affect the IOP in healthy individuals.

Poor perinatal growth impairs baboon aortic windkessel function.

The ability of the aorta to buffer blood flow and provide diastolic perfusion (Windkessel function) is a determinant of cardiovascular health. We have reported cardiac dysfunction indicating downstream vascular abnormalities in young adult baboons who were intrauterine growth restricted (IUGR) at birth as a result of moderate maternal nutrient reduction. Using 3 T MRI, we examined IUGR offspring (eight male, eight female; 5.7 years; human equivalent 25 years) and age-matched controls (eight male, eight female; 5.6 years) to quantify distal descending aortic cross-section (AC) and distensibility (AD). ANOVA showed decreased IUGR AC/body surface area (0.9±0.05 cm2/m2 v. 1.2±0.06 cm2/m2, M±s.e.m., P<0.005) and AD (1.7±0.2 v. 4.0±0.5×10-3/mmHg, P<0.005) without sex difference or group-sex interaction, suggesting intrinsic vascular pathology and impaired development persisting in adulthood. Future studies should evaluate potential consequences of these changes on coronary perfusion, afterload and blood pressure.

Prenatal steroid administration leads to adult pericardial and hepatic steatosis in male baboons.

Developmental programming studies indicate that glucocorticoids modify fetal development. We hypothesized that administration of the synthetic glucocorticoid (sGC) betamethasone to pregnant baboons at doses and stages of fetal life equivalent to human obstetric practice to decrease premature offspring morbidity and mortality, programs lipid metabolism. In 10-year-old male baboons (human equivalent 40) exposed in fetal life to betamethasone or saline, we quantified pericardial fat and hepatic lipid content with magnetic resonance imaging and spectroscopy. sGC offspring delivered at term as do most sGC-exposed human neonates. Pericardial fat thickness (7.7±3.6 mm vs 3.1±1.1 mm, M±s.d.; P=0.022; n=5) and hepatic fatty acids (13.3±11.0% vs 2.5±2.2%; P=0.046; n=5) increased following sGC without birth weight or current body morphometric differences. Our results indicate that antenatal sGC therapy caused abnormal fat deposition and adult body composition in mid-life primate offspring. The concern raised is that this degree of pericardial and hepatic lipid accumulation can lead to harmful local lipotoxicity. In summary, developmental programing by sGC produces a mid-life metabolically obese but normal weight phenotype. Prior studies show sexually dimorphic responses to some programming challenges thus female studies are necessary.

Pain perception during debridement of hypersensitive teeth elicited by two ultrasonic scalers.

OBJECTIVES: The ultrasonic NO PAIN technology (Electro Medical Systems, Nyon, CH) promises minimal pain during debridement due to linear oscillating action combined with a sinusoidal power output and feedback control. The aim of the present study was to measure pain perception on a visual analogue scale (VAS) during supportive periodontal therapy including debridement of hypersensitive teeth. Two ultrasonic scalers were used, one with and one without NO PAIN technology. MATERIAL AND METHODS: In a randomized-controlled clinical study with split-mouth design, 100 hypersensitive teeth matched for air blast hypersensitivity were either treated with the ultrasonic device Piezon Master 700 or the Mini Piezon (both EMS, Nyon, CH). Pain perception during debridement was assessed by a VAS (range 0-10). RESULTS: The average VAS for the test device Piezon Master 700 with NO PAIN technology was 3.16 ± 2.10, and for the control device Mini Piezon without NO PAIN technology 3.40 ± 2.59 (p = 0.490). Placing an arbitrary threshold at the VAS score of 3 for significant pain experience, 60 % of the subjects experienced no significant pain with either instrument. CONCLUSION: No statistically significant difference in perceived pain between the instruments used was found. CLINICAL RELEVANCE: Both ultrasonic devices showed very small pain intensities during debridement of highly hypersensitive teeth and can therefore be recommended for supportive periodontal therapy.

Shade affects responses to drought and flooding - acclimation to multiple stresses in bittersweet (Solanum dulcamara L.).

Plants exposed to environmental stress often respond by a change in their phenotypic traits. These changes in trait expression may alleviate the negative effect of such stress factors. However, if multiple stresses are present, responses are likely to be less predictable and hence do not necessarily correlate to plant performance. This study tested if this expectation was true, by subjecting Solanum dulcamara plants to various simultaneous stress factors. Plants were grown in well-watered conditions, drought or flooding, and exposed to either full light or shade for 4 weeks. Shoot and root biomass, stem morphological parameters, such as height, number of nodes and length of stem internodes, and leaf traits like length, specific leaf area, chlorophyll content and stomatal conductance were determined. Both variation in light and in water availability typically caused slower growth, and resulted in distinct phenotypic changes in stem, leaf and root traits. However, effects of stresses on the expression of traits were not always additive. Instead, some combined stress responses (e.g. leaf size) appeared to be limited by physical or physiological constraints, whereas other responses were opposite to each other (e.g. root:shoot ratio), resulting in an intermediate phenotype in the combined stress treatment. These data suggest that in natural conditions, where combined stress factors are likely to be present, the optimal phenotype may not necessarily be expressed. Responses of plants to multiple stress factors may therefore not be associated with immediate advantages in terms of increased performance.

Evidence and consensus-based (S3) guidelines for the treatment of actinic keratosis: International League of Dermatological Societies in cooperation with the European Dermatology Forum: short version

BACKGROUND: Actinic keratosis (AK) is a frequent health condition attributable to chronic exposure to ultraviolet radiation. Several treatment options are available and evidence based guidelines are missing. OBJECTIVES: The goal of these evidence- and consensus-based guidelines was the development of treatment recommendations appropriate for different subgroups of patients presenting with AK. A secondary aim of these guidelines was the implementation of knowledge relating to the clinical background of AK, including consensus-based recommendations for the histopathological definition, diagnosis and the assessment of patients. METHODS: The guidelines development followed a pre-defined and structured process. For the underlying systematic literature review of interventions for AK, the methodology suggested by the Cochrane Handbook for Systematic Reviews of Interventions, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was adapted. All recommendations were consented during a consensus conference using a formal consensus methodology. Strength of recommendations was expressed based on the GRADE approach. If expert opinion without external evidence was incorporated into the reasoning for making a certain recommendation, the rationale was provided. The Guidelines underwent open public review and approval by the commissioning societies.RESULTS: Various interventions for the treatment of AK have been assessed for their efficacy. The consenting procedure led to a treatment algorithm as shown in the guidelines document. Based on expert consensus, the present guidelines present recommendations on the classification of patients, diagnosis and histopathological definition of AK. Details on the methods and results of the systematic literature review and guideline development process have been published separately. CONCLUSIONS: International guidelines are intended to be adapted to national or regional circumstances (regulatory approval, availability and reimbursement of treatments).(AU)

Evidence- and consensus-based (S3) Guidelines for the Treatment of Actinic Keratosis - International League of Dermatological Societies in cooperation with the European Dermatology Forum - Short version.

BACKGROUND: Actinic keratosis (AK) is a frequent health condition attributable to chronic exposure to ultraviolet radiation. Several treatment options are available and evidence based guidelines are missing. OBJECTIVES: The goal of these evidence- and consensus-based guidelines was the development of treatment recommendations appropriate for different subgroups of patients presenting with AK. A secondary aim of these guidelines was the implementation of knowledge relating to the clinical background of AK, including consensus-based recommendations for the histopathological definition, diagnosis and the assessment of patients. METHODS: The guidelines development followed a pre-defined and structured process. For the underlying systematic literature review of interventions for AK, the methodology suggested by the Cochrane Handbook for Systematic Reviews of Interventions, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was adapted. All recommendations were consented during a consensus conference using a formal consensus methodology. Strength of recommendations was expressed based on the GRADE approach. If expert opinion without external evidence was incorporated into the reasoning for making a certain recommendation, the rationale was provided. The Guidelines underwent open public review and approval by the commissioning societies. RESULTS: Various interventions for the treatment of AK have been assessed for their efficacy. The consenting procedure led to a treatment algorithm as shown in the guidelines document. Based on expert consensus, the present guidelines present recommendations on the classification of patients, diagnosis and histopathological definition of AK. Details on the methods and results of the systematic literature review and guideline development process have been published separately. CONCLUSIONS: International guidelines are intended to be adapted to national or regional circumstances (regulatory approval, availability and reimbursement of treatments).

Erratum to: Resorbable osteosynthetic devices in pediatric traumatology: a prospective series of 24 cases.

Erratum to: Eur J Orthop Surg Traumatol DOI 10.1007/s00590-015-1656-8. The author would like to correct the errors in the publication of the original article. The corrected details are given below for your reading. Second and third authors' given names have been published incorrectly. The correct author names should be D. Popkov and H. Huber. The affiliations of the authors J. M. Poircuitte, D. Popkov, H. Huber, E. Polirsztok and P. Journeau are incorrect. The correct affiliations should be: J. M. Poircuitte, H. Huber, E. Polirsztok and P. Journeau: Service de chirurgie orthopedique pediatrique, Hopital d'enfant, Centre hospitalo-universitaire de Nancy, 5 allee du Morvan, 54500 Vandoeuvre les Nancy, France. D. Popkov: Russian Ilizarov Scientific Center for Restorative Traumatology and Orthopaedics, Kurgan, Russia. Corresponding author e-mail address should be p.journeau@ chu-nancy.fr.

Resorbable osteosynthetic devices in pediatric traumatology: a prospective series of 24 cases.

UNLABELLED: Bioresorbable devices are commonly used in traumatology. The biomechanical stability of these materials has improved in the past decade, and they have proven to be biologically non-hazardous, while their main advantage is that their use avoids reintervention for removal of the device. A prospective monocentric study was conducted: 24 patients presenting with a fracture that was amenable to osteosynthesis by small-diameter screws were included. These comprised ten tibial spine fractures, four osteochondritis dissecans of the distal femur, eight fractures of the medial epicondyle of the distal humerus, and two distal tibial apophyseal fractures. One or more screws were used that were made of a copolymer of poly-L-lactide-poly-D-lactide acid and trimethylene carbonate with a diameter of 2.8 mm. All patients were immobilized with a cast. Clinical and radiographic monitoring was conducted every month. The entire follow-up protocol had a duration of 24 months. One patient with osteochondritis dissecans presented with joint effusion. Joint stiffness at the time of cast removal resolved completely after 4 months, except for with three children (one epicondyle fracture, two tibial spine fractures). No subjective or objective instability could be detected by clinical examination. Radiographic follow-up revealed no secondary displacement, and all of the fractures had healed. No osteolysis was seen around the screws. No growth disturbances were noticed. Bioresorbable materials thus appear to be a suitable alternative approach for certain pediatric fractures. Their use resulted in outcomes similar to traditional techniques in terms of functional properties and bone healing. Although initial costs are presumably slightly higher, by avoiding a removal operation the total financial burden is most likely reduced. LEVEL OF EVIDENCE: III.

Low cytochrome oxidase 4I1 links mitochondrial dysfunction to obesity and type 2 diabetes in humans and mice.

OBJECTIVES: Cytochrome oxidase (COX) dysfunction is associated with mitochondrial oxidative stress. We determined the association between COX expression, obesity and type 2 diabetes. SUBJECTS/METHODS: COX4I1 and COX10 genes were measured in monocytes of 24 lean controls, 31 glucose-tolerant and 67 diabetic obese patients, and 17 morbidly obese patients before and after bariatric surgery. We investigated the effect of caloric restriction and peroxisome proliferator-activated receptor (PPAR) agonist treatment on Cox in obese diabetic mice, and that of diet-induced insulin resistance in Streptozotocin-treated mice. RESULTS: Low COX4I1 was associated with type 2 diabetes in obese patients, adjusting for age, gender, smoking, interleukin-6 and high-sensitivity C-reactive protein, all related to metabolic syndrome (MetS; odds ratio: 6.1, 95% confidence interval: 2.3-16). In contrast, COX10 was low in glucose-tolerant and diabetic obese patients. In morbidly obese patients, COX4I1 was lower in visceral adipose tissue collected at bariatric surgery. In their monocytes, COX4I1 decreased after bariatric surgery, and low COX4I1 at 4 months was associated with MetS at 7 years. In leptin-deficient obese diabetic mice, Cox4i1 was low in white visceral adipose tissue (n=13; P<0.001) compared with age-matched lean mice (n=10). PPARγ-agonist treatment (n=13), but not caloric restriction (n=11), increased Cox4i1 (P<0.001). Increase in Cox4i1 depended on the increase in glucose transporter 4 (Glut4) expression and insulin sensitivity, independent of the increase in blood adiponectin. In streptozotocin-treated mice (three groups of seven mice, diet-induced insulin resistance decreased Cox4i1 and Glut4 (P<0.001 for both). CONCLUSION: COX4I1 depression is related to insulin resistance and type 2 diabetes in obesity. In peripheral blood monocytes, it may be a diagnostically useful biomarker.

BCL2 protein signalling determines acute responses to neoadjuvant chemoradiotherapy in rectal cancer.

UNLABELLED: In locally advanced rectal cancer, neoadjuvant chemoradiotherapy is performed prior to surgery to downstage the tumour. Thirty to 40 % of patients do not respond. Defects in apoptotic machinery lead to therapy resistance; however, to date, no study quantitatively assessed whether B cell lymphoma 2 (BCL2)-dependent regulation of mitochondrial apoptosis, effector caspase activation downstream of mitochondria or a combination of both predicts patient responses. In a cohort of 20 rectal cancer patients, we performed protein profiling of tumour tissue and employed validated ordinary differential equation-based systems models of apoptosis signalling to calculate the ability of cancer cells to undergo apoptosis. Model outputs were compared to clinical responses. Systems modelling of BCL2-signalling predicted patients in the poor response group (p = 0.0049). Systems modelling also demonstrated that rectal cancers depended on BCL2 rather than B cell lymphoma-extra large (BCL(X)L) or myeloid cell leukemia 1 (MCL1) for survival, suggesting that poor responders may benefit from therapy with selective BCL2 antagonists. Dynamic modelling of effector caspase activation could not stratify patients with poor response and did not further improve predictive power. We deliver a powerful patient stratification tool identifying patients who will likely not benefit from neoadjuvant chemoradiotherapy and should be prioritised for surgical resection or treatment with BCL2 antagonists. KEY MESSAGES: Modelling BCL2-family proteins identifies patients unresponsive to therapy. Caspase activation downstream of mitochondria cannot identify these patients. Rectal tumours of poor responders are BCL2- but not BCL-XL-dependent. DR_MOMP allows clinicians to identify patients who would not benefit from therapy. DR_MOMP is also a useful patient stratification tool for BCL2 antagonists.

Expression of somatostatin receptor subtype 2 and subtype 5 in thyroid malignancies.

AIM: To retrospectively analyse the expression of somatostatin receptor subtypes 2 (SSTR 2) and 5 (SSTR 5) in thyroid malignancies, possibly the most relevant subtypes for targeted therapy with somatostatin peptide radioligands. In addition, findings were also correlated with the course of disease. PATIENTS, METHODS: 87 consecutive patients (59 women, 28 men) with thyroid malignancy were included; 52 had papillary carcinoma, 24 follicular carcinoma, six medullary carcinoma, two poorly differentiated carcinoma and three anaplastic carcinoma. After initial therapy 70 (80.5%) patients showed complete remission, 11 (12.6%) patients partial remission with clinical and biochemical signs of residual disease and six (6.9%) patients progressive disease. The immunohistochemical staining results of the primary malignancy for SSTR 2 and SSTR 5 were semiquantitatively assessed and correlated with various outcome parameters. RESULTS: In 10 of 87 (11.49%) thyroid cancer samples SSTR 2 showed positive immunohistochemical expression as compared to 75 of 87 (86.20%) for SSTR 5. All SSTR 2-positive cases expressed SSTR 5. Persistent or recurrent disease was found in 17 of 87 cases (19.54%). Fifty percent (6 /12) of SSTR 5-negative patients showed persistent disease as compared to 14.7 % (11 / 75) of SSTR 5-positive patients: seven of these were exclusively SSTR 5-positive, 4 showed dual expression of SSTR 5 and SSTR 2 (p = 0.01). No case showed only SSTR 2 expression. CONCLUSIONS: SSTR 5 was shown to be the main receptor subtype in the analysed differentiated or anaplastic thyroid malignancies, whereas SSTR 2 was found only in a small percentage. Deficient SSTR expression may indicate higher risk for persistent or recurrent disease after initial therapy. For this reason immunohistochemistry can be considered a prognostic marker which should be further validated in prospective studies.

[Cutaneous Rosai-Dorfman syndrome. Successful therapy with intrralesional corticosteroids]. / Kutanes Rosai-Dorfman-Syndrom. Erfolgreiche Therapie mit intraläsional applizierten Steroiden.

BACKGROUND: Cutaneous Rosai-Dorfman disease is a rare disorder belonging to the spectrum of non-Langerhans cell histiocytoses. It is characterized by dermal and subcutaneous infiltrates of histiocytes as well as accompanying lymphocytes, plasma cells and granulocytes. Because it is so rare, standard therapies have not been established. CASE REPORT: A 27-year-old man showed an excellent response to intralesional corticosteroids after unsuccessful prior treatment with methotrexate, systemic steroids and surgery as well as laser therapy.

Prodromal features for Parkinson's disease--baseline data from the TREND study.

BACKGROUND AND PURPOSE: A number of non-motor features are known to precede motor manifestations of Parkinson's disease (PD). They are supposed to already represent the prodromal neurodegenerative state in those who later develop PD and are thus called prodromal markers. In this study, three prodromal markers, depression, rapid eye movement behaviour disorder (RBD) and hyposmia, were selected and were related to other prodromal features in elderly individuals without PD. METHODS: From the Tübinger Evaluation of Risk Factors for Early Detection of Neurodegeneration (TREND) study, 698 healthy individuals aged 50-80 years reporting one or more of the selected prodromal markers (SPMs), but without neurodegenerative disorders, were evaluated and classified according to the status of prodromal markers. Other prodromal PD-related features were assessed with a 23-item questionnaire and compared between participants with and without the three SPMs. RESULTS: Individuals with the SPMs for PD endorsed more of the additional possible prodromal features of PD than those without; of 23 possible prodromal features, the median number identified amongst participants with no SPMs was two, compared with four with one marker, five with two and seven with three (P < 0.001). Regarding individual SPMs, participants with depression and RBD endorsed five of 23 markers, compared with three for those with hyposmia (P = 0.001). There was no significant increase in the number of prodromal features amongst those with two SPMs compared with those with only one marker. CONCLUSIONS: Individuals with the SPMs for PD report a higher prevalence of other prodromal PD symptoms. This may indicate that these markers can identify individuals at risk for PD.

MALDI-TOF MS for identification of porcine Brachyspira species.

UNLABELLED: The aim of this study consisted in evaluating MALDI-TOF MS as a tool for the identification of the genus Brachyspira (B.) and its relevant species for the pig industry. First, a database was created with 30 control strains, and superspectra for five different porcine Brachyspira species were calculated. In a second step, 67 field isolates were investigated using MALDI-TOF MS, and results were compared to those obtained using nox gene-based RFLP (reference method) and biochemical tests. Among the 67 field isolates, five different Brachyspira species were detected using nox gene-based RFLP analysis. MALDI-TOF MS analysis correctly assigned all isolates to the genus Brachyspira and identified all isolates from B. hyodysenteriae (29/29), B. pilosicoli (11/11), B. intermedia (4/4) and B. innocens (11/11). In terms of B. murdochii, MALDI-TOF MS assigned one of 12 isolates ambiguously as B. innocens/B. murdochii. The results of this study indicate that MALDI-TOF MS facilitates the diagnosis of swine dysentery and porcine intestinal spirochaetosis. SIGNIFICANCE AND IMPACT OF THE STUDY: Current methods for the discrimination of pathogenic Brachyspira hyodysenteriae and Brachyspira pilosicoli from Brachyspira species with low pathogenic potential have proven to be laborious and time-consuming and are therefore not suitable for routine diagnostics. This study describes the evaluation of MALDI-TOF MS for the identification of different porcine Brachyspira species in routine diagnostic laboratories. The results suggest that MALDI-TOF MS is an effective method for the identification of porcine Brachyspira spp. and accelerates diagnosis of swine dysentery and porcine intestinal spirochaetosis.

Continuous capacitance-voltage spectroscopy mapping for scanning microwave microscopy.

A new method, scanning sawtooth capacitance spectroscopy (SSCS), is proposed to measure a map of capacitance/voltage curves (C-V) by applying a low frequency voltage sawtooth signal (20-100 Hz) to the AFM tip while scanning. For this a scanning microwave microscope (SMM) is used to acquire calibrated capacitance data in the high frequency range of 1-20 GHz. While the capacitance is acquired pixel by pixel, the applied voltage signal is recorded as well, and each pixel of the capacitance is assigned the corresponding voltage value. Assuming the voltage variable is smooth over time, adjacent pixels within a scan line will have similar voltage values and a small sequence of neighboring pixels can be combined into a virtual C-V spectroscopy curve. With standard SMM operation parameters roughly 26,000 C-V curves can be acquired within few minutes data acquisition time. The method is demonstrated for n-type and p-type silicon semiconductor samples and can be applied to other samples including new materials and bio-membranes.

Latrepirdine is a potent activator of AMP-activated protein kinase and reduces neuronal excitability.

Latrepirdine/Dimebon is a small-molecule compound with attributed neurocognitive-enhancing activities, which has recently been tested in clinical trials for the treatment of Alzheimer's and Huntington's disease. Latrepirdine has been suggested to be a neuroprotective agent that increases mitochondrial function, however the molecular mechanisms underlying these activities have remained elusive. We here demonstrate that latrepirdine, at (sub)nanomolar concentrations (0.1 nM), activates the energy sensor AMP-activated protein kinase (AMPK). Treatment of primary neurons with latrepirdine increased intracellular ATP levels and glucose transporter 3 translocation to the plasma membrane. Latrepirdine also increased mitochondrial uptake of the voltage-sensitive probe TMRM. Gene silencing of AMPKα or its upstream kinases, LKB1 and CaMKKß, inhibited this effect. However, studies using the plasma membrane potential indicator DisBAC2(3) demonstrated that the effects of latrepirdine on TMRM uptake were largely mediated by plasma membrane hyperpolarization, precluding a purely 'mitochondrial' mechanism of action. In line with a stabilizing effect of latrepirdine on plasma membrane potential, pretreatment with latrepirdine reduced spontaneous Ca(2+) oscillations as well as glutamate-induced Ca(2+) increases in primary neurons, and protected neurons against glutamate toxicity. In conclusion, our experiments demonstrate that latrepirdine is a potent activator of AMPK, and suggest that one of the main pharmacological activities of latrepirdine is a reduction in neuronal excitability.

Multimodal mapping of human skin.

BACKGROUND: The combination of coherent anti-Stokes Raman scattering (CARS), second harmonic generation (SHG) and two-photon excited fluorescence (TPEF) imaging--referred to as multimodal imaging--provides complementary contrast based on molecular vibrations, the structure of various tissue components and endogenous fluorophores, respectively. OBJECTIVES: To present a comprehensive overview of the appearance of human skin in multimodal imaging. METHODS: Multimodal imaging of unstained skin cross-sections of 32 individuals was performed using a laser scanning microscope and picosecond laser pulse for excitation. RESULTS: The epidermis, dermis and subcutis are distinguishable in all three applied modalities, but are unveiled best in multimodal images. While the subcutis is dominated by the CARS signal, predominately SHG and the secondary TPEF signal detect the dermis. In contrast, no SHG signal is detected in the epidermis, whereas CARS and TPEF show equal contributions. Additionally, the appearance of the major skin appendages is described, i.e. the hair follicle, sebaceous and sweat glands, and blood vessels belonging to the vascular system. All four investigated functional units show a characteristic morphochemistry in TPEF and CARS, allowing identification of further subunits, e.g. the major components of the hair follicle, while the SHG signal delineates the localization of the functional units. CONCLUSIONS: Multimodal imaging is a powerful tool to investigate human skin by providing high contrast based on the molecular constitution. It is therefore suggested that multimodal imaging has a high potential in application to dermatological research and clinical diagnostics of various skin alterations.

Activation of executioner caspases is a predictor of progression-free survival in glioblastoma patients: a systems medicine approach.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. GBM cells are highly resistant to apoptosis induced by antitumor drugs and radiotherapy resulting in cancer progression. We assessed whether a systems medicine approach, analysing the ability of tumor cells to execute apoptosis could be utilized to predict the response of GBM patients to treatment. Concentrations of the key proapoptotic proteins procaspase-3, procaspase-9, Smac and Apaf-1 and the antiapopotic protein XIAP were determined in a panel of GBM cell lines and GBM patient tumor resections. These values were used as input for APOPTO-CELL, a systems biological based mathematical model built to predict cellular susceptibility to undergo caspase activation. The modeling was capable of accurately distinguishing between GBM cells that die or survive in response to treatment with temozolomide in 10 of the 11 lines analysed. Importantly the results obtained using GBM patient samples show that APOPTO-CELL was capable of stratifying patients according to their progression-free survival times and predicted the ability of tumor cells to support caspase activation in 16 of the 21 GBM patients analysed. Calculating the susceptibility to apoptosis execution may be a potent tool in predicting GBM patient therapy responsiveness and may allow for the use of APOPTO-CELL in a clinical setting.