Chemometric Approaches for Developing Infrared Nanosensors To Image Anthracyclines.

Generation, identification, and validation of optical probes to image molecular targets in a biological milieu remain a challenge. Synthetic molecular recognition approaches leveraging the intrinsic near-infrared fluorescence of single-walled carbon nanotubes are promising for long-term biochemical imaging in tissues. However, generation of nanosensors for selective imaging of molecular targets requires a heuristic approach. Here, we present a chemometric platform for rapidly screening libraries of candidate single-walled carbon nanotube nanosensors against biochemical analytes to quantify the fluorescence response to small molecules, including vitamins, neurotransmitters, and chemotherapeutics. We further show this method can be applied to identify biochemical analytes that selectively modulate the intrinsic near-infrared fluorescence of candidate nanosensors. Chemometric analysis thus enables identification of nanosensor-analyte "hits" and also nanosensor fluorescence signaling modalities such as wavelength shifts that are optimal for translation to biological imaging. Through this approach, we identify and characterize a nanosensor for the chemotherapeutic anthracycline doxorubicin (DOX), which provides a ≤17 nm fluorescence red-shift and exhibits an 8 µM limit of detection, compatible with peak circulatory concentrations of doxorubicin common in therapeutic administration. We demonstrate the selectivity of this nanosensor over dacarbazine, a chemotherapeutic commonly co-injected with doxorubicin. Lastly, we establish nanosensor tissue compatibility for imaging of doxorubicin in muscle tissue by incorporating nanosensors into the mouse hindlimb and measuring the nanosensor response to exogenous DOX administration. Our results motivate chemometric approaches to nanosensor discovery for chronic imaging of drug partitioning into tissues and toward real-time monitoring of drug accumulation.

Effects of Three Different Exercise Strategies for Optimizing Aerobic Capacity and Skeletal Muscle Performance in Older Adults: A Pilot Study.

This Brief Report describes a pilot study of the effect of 12 weeks of stationary bicycle high-intensity interval training, stationary bicycle moderate-intensity continuous training, and resistance training on cardiorespiratory, muscular, and physical function measures in insufficiently-active older adults (N=14; 66.4±3.9 years; 3 male, 11 female). After baseline testing, participants were randomly assigned to one of the exercise groups. High-intensity interval training and moderate-intensity continuous training had small-to-large effect sizes on cardiorespiratory/endurance and physical function measures, but very small effect sizes on muscular measures. Resistance training had small-to-large effect sizes on cardiorespiratory, muscular, and physical function measures. This pilot study should be interpreted cautiously, but findings suggest that resistance exercise may be the most effective of the three studied exercise strategies for older adults as it can induce beneficial adaptations across multiple domains. These effect sizes can be used to determine optimal sample sizes for future investigations.

Comparison of a Multi-Component Physical Function Battery to Usual Walking Speed for Assessing Lower Extremity Function and Mobility Limitation in Older Adults.

OBJECTIVES: To compare a composite measure of physical function that comprises locomotor and non-locomotor tests (i.e., the Mobility Battery Assessment (MBA)) with traditional measures of mobility (4-m usual gait speed (UGS), six-minute walk (6MW) gait speed, and short physical performance battery (SPPB) score) for assessing lower extremity function and discriminating community dwelling older adults with and without mobility limitations. DESIGN: Cross-sectional, observational study. SETTING: Laboratory-based. PARTICIPANTS: 89 community-dwelling older adults (74.9±6.7). MEASUREMENTS: Using principal component analysis we derived an MBA score for 89 community-dwelling older adults, and quantified 4-m UGS, 6MW gait speed, and SPPB score. The MBA score was based on five lab-based tests. We also quantified self-reported lower extremity function/mobility using the Neuro-QOL Lower Extremity Function-Mobility instrument. Based on this data a continuous score was derived and subjects were classified as "mobility limited" or "non-mobility limited". Correlations between the mobility measures and the Neuro-QOL score were calculated, and ROC curves were constructed to determine the AUC for the mobility measures ability to predict mobility limitations. RESULTS: The MBA had the largest AUC (0.92) for discriminating mobility limitations and exhibited the strongest correlation (0.73) with the Neuro-QOL Lower Extremity Function-Mobility Scale. The worst performing predictors were the 4-meter UGS and stair climb power both with an AUC of 0.8 for discriminating mobility limitations, and a low correlation with Neuro-QOL Lower Extremity Function Scale of 0.39 and 0.46, respectively. CONCLUSION: The MBA score moderately improves the magnitude of correlation and discrimination of mobility limitation in older adults than singular, standard tests of mobility.

Recurrent intraplate tectonism in the new madrid seismic zone.

For the first time, New Madrid seismicity can be linked to specific structural features that have been reactivated through geologic time. Extensive seismic reflection profiling reveals major faults coincident with the main earthquake trends in the area and with structural deformation apparently caused by repeated episodes of igneous activity.

Relationship of Physical Frailty to Phosphocreatine Recovery in Muscle after Mild Exercise Stress in the Oldest-Old Women.

BACKGROUND: Physical frailty is a clinical syndrome associated with aging and manifesting as slowness, weakness, reduced physical activity, weight loss, and/or exhaustion. Frail older adults often report that their major problem is "low energy", and there is indirect evidence to support the hypothesis that frailty is a syndrome of dysregulated energetics. We hypothesized that altered cellular energy production underlies compromised response to stressors in the frail. METHODS: We conducted a pilot study to assess muscle energetics in response to a mild isometric exercise challenge in women (n=30) ages 84-93 years. The frailty status was assessed by a validated physical frailty instrument. Localized phosphorus (P31) magnetic resonance spectroscopy with a 1.5T magnet was used to assess the kinetics of Phosphocreatine recovery in the tibialis anterior muscle following maximal isometric contraction for 30 seconds. RESULTS: Phosphocreatine recovery following exertion, age-adjusted, was slowest in the frail group (mean=189 sec; 95%CI: 150,228) compared to pre-frail (mean=152 sec; 95%CI: 107,197) and nonfrail subjects (mean=132 sec; 95%CI: 40,224). The pre-frail and frail groups had 20 sec (95%CI: -49,89) and 57 sec (95%CI: -31,147) slower phosphocreatine recovery, respectively, than the non-frail. This response was paralleled by dysregulation in glucose recovery in response to oral glucose tolerance test in women from the same study population. CONCLUSIONS: Impaired muscle energetics and energy metabolism might be implicated in the physical frailty syndrome.

In vivo results for interstitial laser application in thyroid gland.

OBJECTIVE: Aim of this study was to evaluate the potential of denaturation of hormone active tissue in the thyroid gland by laser induced interstitial thermotherapy (LITT) as a treatment of autonomous hyperthyroidism. MATERIALS AND METHODS: An interstitial thyroid laser application (Nd:YAG 1064 nm, 5W, 2 min) was performed in 5 pigs. During laser application, the laryngeal recurrent nerve was controlled electro-physiologically. Postoperatively, TSH, total T(3) (TT(3)) and free T(4) (FT(4)) were measured regularly. After a follow-up period of up to 6 weeks, pigs were sacrificed and the thyroid glands were evaluated histological. RESULTS: A malfunction of the nerve due to laser treatment was not detected. During the first postoperative week there was a decrease of both FT(4) and TSH whereas TT(3) showed an extreme decline of its plasma levels reaching nearly the detection limit. All values showed a recovery to their initial levels during an interval of 10 days and than increased to levels sometimes higher than baseline. The coagulation zones were demarcated clearly towards normal tissue with increasing fibrosis of the treated areas. CONCLUSION: Interstitial thyroid ablation using a Nd:YAG laser is a minimal invasive, safe and effective procedure. Further evaluation including long term follow-up in humans is needed to confirm these results.

Additivity of inhibitory effects in multidrug combinations.

From natural ecology1-4 to clinical therapy5-8, cells are often exposed to mixtures of multiple drugs. Two competing null models are used to predict the combined effect of drugs: response additivity (Bliss) and dosage additivity (Loewe)9-11. Here, noting that these models diverge with increased number of drugs, we contrast their predictions with growth measurements of four phylogenetically distant microorganisms including Escherichia coli, Staphylococcus aureus, Enterococcus faecalis and Saccharomyces cerevisiae, under combinations of up to ten different drugs. In all species, as the number of drugs increases, Bliss maintains accuracy while Loewe systematically loses its predictive power. The total dosage required for growth inhibition, which Loewe predicts should be fixed, steadily increases with the number of drugs, following a square-root scaling. This scaling is explained by an approximation to Bliss where, inspired by R. A. Fisher's classical geometric model12, dosages of independent drugs add up as orthogonal vectors rather than linearly. This dose-orthogonality approximation provides results similar to Bliss, yet uses the dosage language as in Loewe and is hence easier to implement and intuit. The rejection of dosage additivity in favour of effect additivity and dosage orthogonality provides a framework for understanding how multiple drugs and stressors add up in nature and the clinic.

Effects of Running Wheel Activity and Dietary HMB and ß-alanine Co-Supplementation on Muscle Quality in Aged Male Rats.

OBJECTIVE: Loss of skeletal muscle function is linked to increased risk for loss of health and independence in older adults. Dietary interventions that can enhance aging muscle function, alone or in combination with exercise, may offer an effective way to reduce these risks. The goal of this study was to evaluate the muscular effects of beta-hydroxy-beta-methylbutyrate (HMB) and beta-alanine (ß-Ala) co-supplementation in aged Sprague-Dawley rats with voluntary access to running wheels (RW). METHODS: Aged (20 months) rats were housed with ad libitum access to RW while on a purified diet for 4 weeks, then balanced for RW activity and assigned to either a control or an experimental diet (control + HMB and ß-Ala) for the next 4 weeks (n = 10/group). At the end of the study, we assessed muscle size, in situ force and fatigability in the medial gastrocnemius muscles, as well as an array of protein markers related to various age- and activity-responsive signaling pathways. RESULTS: Dietary HMB+ß-Ala did not improve muscle force or fatigue resistance, but a trend for increased muscle cross-sectional area (CSA) was observed (P = 0.077). As a result, rats on the experimental diet exhibited reduced muscle quality (force/CSA; P = 0.032). Dietary HMB+ß-Ala reduced both the abundance of PGC1-α (P = 0.050) and the ratio of the lipidated to non-lipidated forms of microtubule-associated protein 1 light chain 3 beta (P = 0.004), markers of mitochondrial biogenesis and autophagy, respectively. Some alterations in myostatin signaling also occurred in the dietary HMB+ß-Ala group. There was an unexpected difference (P = 0.046) in RW activity, which increased throughout the study in the animals on the control diet, but not in animals on the experimental diet. CONCLUSIONS: These data suggest that the short-term addition of dietary HMB+ß-Ala to modest physical activity provided little enhancement of muscle function in this model of uncomplicated aging.

IL-6 expression induced by adenosine A2b receptor stimulation in U373 MG cells depends on p38 mitogen activated kinase and protein kinase C.

Adenosine binds to a class of G-protein coupled receptors, which are further distinguished as A(1), A(2a), A(2b) and A(3) adenosine receptors. As we have shown earlier, the stable adenosine analogue NECA (N6-(R)-phenylisopropyladenosine) stimulates IL-6 expression in the human astrocytoma cell line U373 MG via the A(2b) receptor. The mechanism by which NECA promotes astrocytic IL-6 expression has not been identified. By using various inhibitors of signal transduction, we found that p38 mitogen-activated protein kinases (MAPK) activation (inhibitor SB202190), but not extracellular signal-regulated kinase (ERK) (PD98059) and c-jun N-terminal kinase (JNK)(SP600125), is essential in the NECA-induced signalling cascade that leads to the increase in IL-6 synthesis in U373 MG cells. Results obtained with protein kinase C (PKC) inhibitors that have different substrate specificities, indicated that the PKC delta and epsilon isoforms are also involved in adenosine receptor A(2b) dependent upregulation of IL-6 expression. This is supported by the fact that NECA induced the activation of PKC delta and epsilon in U373 MG cells.

Who has nightmares? The personality of the lifelong nightmare sufferer.

Twelve lifelong nightmare sufferers, 12 vivid dreamers who had no nightmares, and 12 persons who had neither nightmares nor vivid dreams were studied in a series of structured interviews, psychological tests, and other tests. The group with nightmares had significantly higher scores on the "psychotic" side of the Minnesota Multiphasic Personality Inventory profile than the other two groups, scored higher on a "boundary deficit" score of the Rorschach test, and had more first- and second-degree relatives with nightmares, psychological problems, and psychiatric hospitalization. There were no significant differences between the groups with vivid and nonvivid dreams. On interview, the frequent nightmare sufferers were a group of sensitive, open persons who had features of the "schizophrenic spectrum disorders," but who also had artistic and creative tendencies and interests, in contrast to the other groups. These results confirm and extend our previous findings in a group of 38 frequent nightmare sufferers.

A Pilot Study of Age-Related Changes in the Sphingolipid Composition of the Rat Sarcoplasmic Reticulum.

BACKGROUND: Muscle strength declines more rapidly than muscle size, manifesting as a loss of muscle quality. One putative contributor to this impairment of muscle quality is impaired sarcoplasmic reticulum (SR) function. OBJECTIVES: The principal objective of this study was to characterize the sphingolipid composition of the SR in adult and aging rat muscles. A secondary, exploratory objective was to test for associations between SR sphingolipids and SR function (i.e., Ca2+ release). DESIGN: Using an animal model, the objectives were evaluated in a pre-clinical, cross-sectional study. SETTING: Data were collected in an academic research laboratory. PARTICIPANTS: Medial gastrocnemius muscles of adult (n=8; 7-8 months) and aged (n=8; 24-25 months), male F344/BN hybrid rats were processed to extract SR. MEASUREMENTS: Sphingolipids in the SR were measured using tandem mass spectrometry. Fatty acid concentrations within the major sphingolipid classes were evaluated via Principal Component Analysis (PCA). In a subset of samples, SR Ca2+ release rates were determined using fluorometric methods, and associations with specific (based on results of PCA) fatty acid concentrations were evaluated. RESULTS: Aging SR showed an overall decline in the ratio of unsaturated to saturated fatty acids. Age-specific differences were observed for hexosylceramide and ceramide-1-phosphate. Within subset of samples with SR Ca2+ release data, a significant negative association between Ca2+ release and C1P18:0 and trends for positive associations with hexCER24:0 and 24:1 were observed. CONCLUSIONS: These preliminary, pre-clinical data suggest that changes in SR sphingolipids may play a role in age-related impairment of muscle function. Further work is needed to explore this hypothesis, as SR sphingolipids may prove a fruitful target for interventions, be they physical (i.e., exercise), nutritional or pharmacological.

A preliminary study of the personality of the nightmare sufferer: relationship to schizophrenia and creativity?

Through psychiatric interviews and psychological tests the authors studied 38 adults who reported experiencing at least one nightmare per week. Nearly all of the subjects had a lifelong history of frequent nightmares. Four of the subjects met DSM-III criteria for schizophrenia, 9 met the criteria for borderline personality, and 6 met the criteria for schizotypal personality. The others had no specific diagnosis, and none of the subjects had a diagnosis of typical neurosis. Many had mentally ill relatives. Most had artistic interests and talents. These nightmare sufferers may be seen as unusually vulnerable, with a potential for mental illness--especially schizophrenia--as well as a potential for artistic achievement.

Adverse effects of single therapeutic doses of diazepam on performance in normal geriatric subjects: relationship to plasma concentrations.

Elderly normal volunteers (N = 12, mean age 70.4 years) were administered placebo or diazepam 2.5, 5, 10 mg in four consecutive sessions separated by at least a 1-week interval. Memory and psychomotor performance and plasma diazepam concentrations were assessed at baseline and at 1 and 3 h following drug administration. Significant impairments were found in response to all doses of diazepam. The maximum impairment occurred at 1 h, which coincided with the highest plasma concentration of the drug.

Effects of activation frequency and force on low-frequency fatigue in human skeletal muscle.

No comparison of the amount of low-frequency fatigue (LFF) produced by different activation frequencies exists, although frequencies ranging from 10 to 100 Hz have been used to induce LFF. The quadriceps femoris of 11 healthy subjects were tested in 5 separate sessions. In each session, the force-generating ability of the muscle was tested before and after fatigue and at 2, approximately 13, and approximately 38 min of recovery. Brief (6-pulse), constant-frequency trains of 9.1, 14.3, 33.3, and 100 Hz and a 6-pulse, variable-frequency train with a mean frequency of 14.3 Hz were delivered at 1 train/s to induce fatigue. Immediately postfatigue, there was a significant effect of fatiguing protocol frequency. Muscles exhibited greater LFF after stimulation with the 9.1-, 14.3-, and variable-frequency trains. These three trains also produced the greatest mean force-time integrals during the fatigue test. At 2, approximately 13, and approximately 38 min of recovery, however, the LFF produced was independent of the fatiguing protocol frequency. The findings are consistent with theories suggesting two independent mechanisms behind LFF and may help identify the optimal activation pattern when functional electrical stimulation is used.

Episodic secretion of LH and FSH after ovariectomy. Secretory patterns in response to estrogen and progesterone.

PIP: Patterns of LH and FSH secretion were studied in menopausal and ovariectomized subjects by frequent sampling and the influence of ovarian steroids upon these patterns was observed. Subjects were 5 women who had been subjected to bilateral oophorectomy. At 8:00 AM of Study Day 1 (control day), after fasting since midnight, 5 ml of venous blood was drawn and samples were taken at 20 minute intervals thereafter for a period of 8 hours. Patency of the needle was maintained by a slow infusion of normal saline. Blood serum was stored at - 20 degrees C. The next day blood samples were similarly collected for 2 hours. Then, in 2 patients, at 10:00 AM estradiol benzoate 1 mg was administered in a single dose, after which blood samples were collected at 20 minute intervals for an additional 6 hours. On Day 3 the same procedure was followed, except that at 10:00 AM progesterone 100 mg was given in a single intravenous dose. In 3 other patients the order of steroid administration was reversed so that progesterone was given on Study day 2 and estradiol on Day 3. Serum LH and FSH concentrations were determined by double antibody radioimmunoassays. Serum LH and FSH concentrations were increased in all patients. During control periods serum LH levels fluctuated periodically in all subjects. Serum FSH concentration varied episodically in 2 patients. No synchronous pattern was noted either before or after the administration of the drugs. After estradiol was administered on Day 2 to 2 patients, serum LH concentrations declined 39-55% from pretreatment levels and serum FSH levels decreased 15-20%. In these patients episodic increases in both LH and FSH values were observed even after estradiol injection. When progesterone was given on Day 2 and estradiol on Day 3, serum LH concentrations declined promptly. Fluctuation of LH levels were apparent in 2 of the 3 patients. FSH levels declined in only 1. Progesterone alone had no effect on FSH levels. Steroids seem to modify release of gonadotrophin rather than exert sole control over gonadotrophin release.^ieng

Reflex modulation of airflow dynamics through the upper airway.

We studied the effect of respiratory reflexes on maximal inspiratory flow (VImax) and its mechanical determinants, pharyngeal critical pressure (Pcrit) and nasal resistance, in an isolated feline upper airway preparation. Chemoreceptor reflexes were evaluated by varying inspired oxygen and end-tidal CO2 concentrations. At each gas concentration, we found that changes in VImax were related to changes in Pcrit. As CO2 increased, Pcrit became increasingly subatmospheric (P < 0.02), indicating reductions in pharyngeal collapsibility. In contrast, progressive hypoxia had no effect on Pcrit. We then examined the effects of vagal afferents and upper airway mucosal receptors on airflow dynamics at three levels of CO2. We confirmed that CO2 increased VImax (P < 0.01) and decreased Pcrit to more subatmospheric levels (P < 0.05) in both the presence and absence of vagal and airway mucosal afferent activity. Moreover, airway mucosal afferents led to smaller reductions in Pcrit (a less collapsible airway) (P < 0.05), whereas vagal afferents led to a larger increase in Pcrit (a more collapsible pharynx) under hypercapnic conditions (P < 0.01). We conclude that CO2 had a major effect on pharyngeal collapsability and that its effect was modulated by vagal and mucosal afferents. We speculate that the sensitivity and threshold to reflex CO2 responses play a major role in the maintenance of airway patency.

Corneal morphology in vitro after superficial keratectomy with q-switched Er:YSGG and free-running Er:YAG lasers.

PURPOSE: Examination of morphology in corneal ablation induced by a q-switched Er:YSGG (2.79 microm) laser and a free-running Er:YAG laser (2.94 microm). METHODS: Defined ablation of 6-mm diameter and 15, 30, 55, 90, and 120-microm depth was performed on freshly enucleated swine eyes. Er:YSGG laser parameters: fluence 1.6 J/cm2, frequency 6 Hz, spot-size 465 microm FWHM, scanning-mode, pulse number 1520 to 6210. Er:YAG laser parameters: fluence 3 J/cm2, frequency 1.5 Hz, spotsize 6 mm, wide area ablation, pulse number 2 to 13. Corneal morphology was analyzed by gross photography, histology, scanning electron microscopy, and scanning nearfield acoustic microscopy. RESULTS: Histology showed thermal damage of 5 to 15 microm in depth caused by the Er:YSGG laser in comparison with 10 to 20 microm by the Er:YAG laser. Average roughness of the ablated surface measured with scanning nearfield acoustic microscopy was 20 to 40 microm for the Er:YSGG laser and 5 to 15 microm for the Er:YAG laser. These data confirm the subjective impression of images created by scanning electron microscopy and gross photography. CONCLUSIONS: Although the Er:YAG laser system appeared to demonstrate a smoother corneal surface than the q-switched Er:YSGG laser, the thermal damage in either case poses a potential limitation for clinical use in lamellar refractive surgery.

Variation in transcript abundance during somatic embryogenesis in gymnosperms.

Somatic embryogenesis of Norway spruce (Picea abies L.) is a versatile model system to study molecular mechanisms regulating embryo development because it proceeds through defined developmental stages corresponding to specific culture treatments. Normal embryonic development involves early differentiation of proembryogenic masses (PEMs) into somatic embryos, followed by early and late embryogeny leading to the formation of mature cotyledonary embryos. In some cell lines there is a developmental arrest at the PEM-somatic embryo transition. To learn more about the molecular mechanisms regulating embryogenesis, we compared the transcript profiles of two normal lines and one developmentally arrested line. Ribonucleic acid, extracted from these cell lines at successive developmental stages, was analyzed on DNA microarrays containing 2178 expressed sequence tags (ESTs) (corresponding to 2110 unique cDNAs) from loblolly pine (Pinus taeda L.). Hybridization between spruce and pine species on microarrays has been shown to be effective (van Zyl et al. 2002, Stasolla et al. 2003). In contrast to the developmentally arrested line, the early phases of normal embryo development are characterized by a precise pattern of gene expression, i.e., repression followed by induction. Comparison of transcript levels between successive stages of embryogenesis allowed us to identify several genes that showed unique expression responses during normal development. Several of these genes encode proteins involved in detoxification processes, methionine synthesis and utilization, and carbohydrate metabolism. The potential role of these genes in embryo development is discussed.

In-season management of shoulder pain in a collegiate swimmer: a team approach.

Shoulder pain is a common problem among competitive swimmers, often limiting their ability to train and compete. Although a number of rehabilitation programs for shoulder injuries have been reported in the literature, there is a lack of objective data regarding the effectiveness of these protocols in the competitive swimming population. This case report describes the evaluation and treatment of shoulder pain in an NCAA Division I swimmer during the competitive season. Once a physical therapy diagnosis was made, a plan of care was developed to address each component impairment. This required the input of the team trainers, the team physician, and an orthopaedic surgeon. A chief component of the athlete's rehabilitation involved allowing the athlete to compete, but not practice. Excellent results were achieved, as evidenced by symptom reduction and swimming performance. This case report highlights the interactive, team approach necessary for optimal management of the injured athlete.

[Dynamic interstitial laser application for therapy of secondary liver tumors. An animal experiment study]. / Dynamische interstitielle Laserapplikation zur Therapie sekundärer Lebertumoren. Eine tierexperimentelle Studie.

Laser-induced interstitial thermotherapy (LITT) is a promising method of treating different types of tumors. To increase the effectiveness of LITT, a new thermo-controlled application system for minimal invasive intervention was designed. This laser system consists of a laser applicator 3 mm in diameter, insertion equipment and an Nd:YAG laser source. The power of the laser source is controlled dynamically by thermosensors in a water-cooling system of the laser applicator. In in vivo experiments in five pigs, within 10 min we found homogeneous coagulation regions in the liver that were of 3 cm and 5 cm in diameter. Via ultrasound we observed in real time the increasing coagulation zone that appeared as a hyperechogenic halo. However, due to perifocal edema, the real coagulation area was smaller than detected by ultrasound. Macroscopically and microscopically, the coagulation zones showed well-demarcated borders of the coagulation lesions, and the surrounding tissue appeared vital. The reparative reaction after irradiation was early fibrosis. In the course of 4 weeks, the surrounding scar capsule, containing fibrocytes, biliary ductules and collagen fibers enlarged. As a result, the coagulation necrosis became more and more fragmented between collagen fibers and was largely resorbed. The absence of complications in our animal experiments suggest that the technique of thermo-controlled laser light application is safe and useful in therapy for metastases that are not resectable.