Antitumor effect of nanophotothermolysis mediated by zinc phthalocyanine particles.

Nanophotothermolysis (NPhT) effect is considered to be an approach for the development of highly selective modalities for anticancer treatment. Herein, we evaluated an antitumor efficacy of NPhT with intravenously injected zinc phthalocyanine particles (ZnPcPs) in murine subcutaneous syngeneic tumor models. In S37 sarcoma-bearing mice a biodistribution of ZnPcPs was studied and the high antitumor efficacy of ZnPcPs-mediated NPhT was shown, including a response of metastatic lesions. The morphological investigation showed the main role of a local NPhT-induced vascular damage in the tumor growth and tumor spread inhibition. Murine tumors of different histological origin were not equally sensitive to the treatment. The results demonstrate a potential of ZnPcPs-mediated NPhT for treatment of surface tumors.

The embodied typist: Bimanual actions are modulated by words' implied motility and number of evoked limbs.

The planning and execution of manual actions can be influenced by concomitant processing of manual action verbs. However, this phenomenon manifests in varied ways throughout the literature, ranging from facilitation to interference effects. Suggestively, stimuli across studies vary randomly in two potentially relevant variables: verb motility and effector quantity (i.e., the amount of movement and the number of hands implied by the word, respectively). Here we examine the role of these factors during keyboard typing, a strategic bimanual task validated in previous works. Forty-one participants read and typed high and low motility items from four categories: bimanual, unimanual, and non-manual action verbs, as well as minimally motoric verbs. Motor planning and execution were captured by first-letter lag (the lapse between word presentation and first keystroke) and whole-word lag (the lapse between the first and last keystroke). We found that verb motility modulated action planning and execution, both stages being delayed by high (relative to low) motility verbs. Effector quantity also influenced both stages, which were facilitated by bimanual verbs relative to unimanual verbs and non-manual verbs (this effect being confined to high motility items during action execution). Accordingly, motor-language coupling effects seem sensitive to words' implied motility and number of evoked limbs. These findings refine our understanding of how semantics influences bodily movement.

[Efficient Use of Corneal Grafts through Multimodal Donor Tissue Splitting]. / Effiziente Verwendung von Hornhauttransplantaten durch multimodales Spendergewebesplitting.

BACKGROUND: The reduced availability of corneal donor tissue in Ukraine requires the most effective use of the available grafts. The present work describes and evaluates a method to obtain several small diameter corneal grafts from a single donor cornea ("multimodal donor tissue splitting"). MATERIAL AND METHODS: This retrospective cohort study includes keratoplasty procedures performed at the Department of Corneal Pathology, State Institution, "The Filatov Institute of Eye Diseases and Tissue Therapy of the National Academy of Medical Sciences of Ukraine", Odessa, Ukraine. The method of graft preparation includes either lamellar dissection of the entire graft or partial lamellar dissection to obtain two lamellar and/or full-thickness grafts. Grafts were not only cut in a circular manner, but the individual shape was also adjusted to match the shape of non-circular corneal defects. RESULTS: A total of 324 keratoplasties between January 2016 and December 2017, using 270 grafts, were included. In 54 cases (including 34 emergency situations), one transplant was used for two recipients. Of these, 43 were therapeutic keratoplasties and 11 peripheral lamellar keratoplasties due to grade III - IV recurrent pterygia. In two cases, two grafts for one patient were dissected from a single donor cornea. Out of 43 patients with curative keratoplasty, visual acuity improved in 28 eyes (65.1%) or remained unchanged in 15 eyes (34.9%). Postoperative visual acuity was dependent on the initial state of the eye, the localisation, the depth and the area of the corneal defect. In eyes with peripheral corneal localisation of ulcerations, even in the presence of corneal perforation, good functional results were obtained. CONCLUSION: If two or more grafts are obtained from a single donor cornea for different kinds of keratoplasty procedures, this reduces the need for corneal graft tissue and, consequently, the cost of preservation. Especially in regions with a high shortage of donor tissue, this provides additional tissue capacities for emergency situations.

How words ripple through bilingual hands: Motor-language coupling during L1 and L2 writing.

The speed of our hand movements can be affected by concurrent processing of manual action verbs (MaVs). Whereas this phenomenon is well established for native languages (L1s), it remains underexplored in late foreign languages (L2s), especially during highly automatized tasks. Here we timed keystroke activity while Spanish-English bilinguals copied MaVs, non-manual action verbs, and non-action verbs in their L1 and L2. Motor planning and execution dynamics were indexed by first-letter lag (the time-lapse between word presentation and first keystroke) and whole-word lag (the time-lapse between first and last keystroke), respectively. Despite yielding no effects on motor planning, MaVs facilitated typing execution in L1 but delayed it in L2, irrespective of the subjects' typing skills, age of L2 learning, and L2 competence. Therefore, motor-language coupling effects seem to be present in both languages though they can arise differently in each. These results extend language grounding models, illuminating the role of embodied mechanisms throughout life.

Motor-system dynamics during naturalistic reading of action narratives in first and second language.

Do embodied semantic systems play different roles depending on when and how well a given language was learned? Emergent evidence suggests that this is the case for isolated, decontextualized stimuli, but no study has addressed the issue considering naturalistic narratives. Seeking to bridge this gap, we assessed motor-system dynamics in 26 Spanish-English bilinguals as they engaged in free, unconstrained reading of naturalistic action texts (ATs, highlighting the characters' movements) and neutral texts (NTs, featuring low motility) in their first and second language (L1, L2). To explore functional connectivity spread over each reading session, we recorded ongoing high-density electroencephalographic signals and subjected them to functional connectivity analysis via a spatial clustering approach. Results showed that, in L1, AT (relative to NT) reading involved increased connectivity between left and right central electrodes consistently implicated in action-related processes, as well as distinct source-level modulations in motor regions. In L2, despite null group-level effects, enhanced motor-related connectivity during AT reading correlated positively with L2 proficiency and negatively with age of L2 learning. Taken together, these findings suggest that action simulations during unconstrained narrative reading involve neural couplings between motor-sensitive mechanisms, in proportion to how consolidated a language is. More generally, such evidence addresses recent calls to test the ecological validity of motor-resonance effects while offering new insights on their relation with experiential variables.

Too late to be grounded? Motor resonance for action words acquired after middle childhood.

Though well established for languages acquired in infancy, the role of embodied mechanisms remains poorly understood for languages learned in middle childhood and adulthood. To bridge this gap, we examined 34 experiments that assessed sensorimotor resonance during processing of action-related words in real and artificial languages acquired since age 7 and into adulthood. Evidence from late bilinguals indicates that foreign-language action words modulate neural activity in motor circuits and predictably facilitate or delay physical movements (even in an effector-specific fashion), with outcomes that prove partly sensitive to language proficiency. Also, data from newly learned vocabularies suggest that embodied effects emerge after brief periods of adult language exposure, remain stable through time, and hinge on the performance of bodily movements (and, seemingly, on action observation, too). In sum, our work shows that infant language exposure is not indispensable for the recruitment of embodied mechanisms during language processing, a finding that carries non-trivial theoretical, pedagogical, and clinical implications for neurolinguistics, in general, and bilingualism research, in particular.

[Emergency Keratoplasty with Porcine Xenografts in Necrotizing Keratitis]. / Notfallkeratoplastik mit porcinen Xenotransplantaten bei nekrotisierender Keratitis.

Background The great shortage of donor material in Ukraine makes it necessary to find additional sources of transplant material. A possible suitable material are the porcine corneas, as they are similar in structure and biomechanical parameters to the human cornea. The purpose of our study was to analyze the results of therapeutic keratoplasty (KP) with keratoxenotransplants from cryolyophilized porcine corneas in patients with severe necrotizing keratitis. Methods A retrospective analysis of 32 xenotransplantations patients with severe necrotizing keratitis (17 lamellar, 6 stepped perforating, 4 perforating, 5 "biological coverage" according to Puchkovskaya) was completed. Results All eyes could be preserved, but the graft was rejected in all eyes. A semitransparent xenograft (XG) was achieved in 9 patients (33.3%). The best results were obtained after lamellar XKP with an XT diameter of 3.5 - 6.5 mm. Lamellar XTs with larger diameters (7.0 - 10.0 mm) were opaque. Postoperatively, the intensity of the inflammatory response after stepped XKP was slightly lower than that of the classical perforating XKP. A new KP with human corneas had to be performed in 5 patients, in one case combined with an antiglaucomatous operation and in another case with cataract extraction. Antiglaucomatous surgery had to be performed in 5 patients (15.6%). Conclusion In the absence of human donor corneas, a porcine keratoxenoimplant can be used as temporary therapeutic keratoplasty in case of emergency stop the inflammation process and to save the eye. In cases of keratoxenoimplant, a poor visual outcome is expected.

The search for the best infantry boot.

BACKGROUND: The combat role of the twenty-first century infantry soldier has changed and accordingly their boots should evolve to meet these new needs and maximize soldier performance. OBJECTIVE: To evaluate injuries and durability of the hot weather infantry boots (HWIB) in elite infantry training and assess the initial performance of newly designed Israeli infantry boots (NDIB). METHODS: In Phase 1, the durability of the HWIB during elite infantry training was evaluated at weeks 10, 19 and 64 in a cohort of 67 recruits. At each exam recruits removed their boots which were assessed for wear and integrity and photographed. The number of times recruits changed their boots was recorded. In Phase 2, foot injuries were assessed in a cohort of 73 elite infantry recruits wearing HWIB. In Phase 3, 65 infantry recruits were issued the NDIB. Recruits feet were measured for width and shoe size using the Brannock device and then followed for problems associated with their boots. Foot lesions were document by photographs. RESULTS: Phase 1: The mean longevity of HWIB in training was 5.2 ± 0.2 (SE) months, (95 % CI 4.83-5.61). Phase 2: 38 % of the elite infantry recruits wearing HWIB had at least one complaint and 31 (42 %) were found to have boot related injuries in a total of 56 injured areas. Phase 3: The mean predicted boot size (42.8 ± 1.7) based on Brannock measurements, was less than the size of the NDIB actually worn, 43.1 ± 1.6. Only 34.8 % of the feet were width D (the standard shoe width). At 9 day follow up, 55 of the 65 recruits who wore NDIB reported at least one problem with them (85 %, p < 0.0001, compared to HWIB). By 3 weeks, all but five recruits had returned to wearing the HWIB. Of the recruits wearing NDIB, 47 (72 %) were found to have had at least one boot related injury with a total number of 180 injured foot areas (p = 0.0004, compared to HWIB). CONCLUSIONS: The HWIB was well tolerated by the elite infantry recruits and associated with significantly less foot injuries than the NDIB. The longevity of the HWIB in demanding elite infantry training was five months. Trial registration: NCT02810002 retrospectively registered June 22, 2016.

Circulation and distribution of gold nanoparticles and induced alterations of tissue morphology at intravenous particle delivery.

Kinetics, biodistribution, and histological studies were performed to evaluate the particle-size effects on the distribution of 15 nm and 50 nm PEG-coated colloidal gold (CG) particles and 160 nm silica/gold nanoshells (NSs) in rats and rabbits. The above nanoparticles (NPs) were used as a model because of their importance for current biomedical applications such as photothermal therapy, optical coherence tomography, and resonance-scattering imaging. The dynamics of NPs circulation in vivo was evaluated after intravenous administration of 15 nm CG NPs to rabbit, and the maximal concentrations of gold were observed 15-30 min after injection. Rats were injected in the tail vein with PEG-coated NPs (about 0.3 mg Au/kg rats). 24 h after injection, the accumulation of gold in different organs and blood was determined by atomic absorption spectroscopy. In accordance with the published reports, we observed 15 nm particles in all organs with rather smooth distribution over liver, spleen and blood. By contrast, the larger NSs were accumulated mainly in the liver and spleen. For rabbits, the biodistribution was similar (72 h after intravenous injection). We report also preliminary data on the light microscopy and TEM histological examination that allows evaluation of the changes in biotissues after gold NPs treatment.

Tachycardia-induced early afterdepolarizations: insights into potential ionic mechanisms from computer simulations.

Although early afterdepolarizations (EADs) are classically thought to occur at slow heart rates, mounting evidence suggests that EADs may also occur at rapid heart rates produced by tachyarrhythmias, due to Ca overload of the sarcoplasmic reticulum (SR) leading to spontaneous SR Ca release. We hypothesized that the mechanism of tachycardia-induced EADs depends on the spatial and temporal morphology of spontaneous SR Ca release, and tested this hypothesis in computer simulations using a ventricular action potential mathematical model. Using two previously suggested spontaneous release morphologies, we found two distinct tachycardia-induced EAD mechanisms: one mechanistically similar to bradycardia-induced EADs, the other to delayed afterdepolarizations (DADs).

Effects of early afterdepolarizations on reentry in cardiac tissue: a simulation study.

Early afterdepolarizations (EADs) are classically generated at slow heart rates when repolarization reserve is reduced by genetic diseases or drugs. However, EADs may also occur at rapid heart rates if repolarization reserve is sufficiently reduced. In this setting, spontaneous diastolic sarcoplasmic reticulum (SR) Ca release can facilitate cellular EAD formation by augmenting inward currents during the action potential plateau, allowing reactivation of the window L-type Ca current to reverse repolarization. Here, we investigated the effects of spontaneous SR Ca release-induced EADs on reentrant wave propagation in simulated one-, two-, and three-dimensional homogeneous cardiac tissue using a version of the Luo-Rudy dynamic ventricular action potential model modified to increase the likelihood of these EADs. We found: 1) during reentry, nonuniformity in spontaneous SR Ca release related to subtle differences in excitation history throughout the tissue created adjacent regions with and without EADs. This allowed EADs to initiate new wavefronts propagating into repolarized tissue; 2) EAD-generated wavefronts could propagate in either the original or opposite direction, as a single new wave or two new waves, depending on the refractoriness of tissue bordering the EAD region; 3) by suddenly prolonging local refractoriness, EADs caused rapid rotor displacement, shifting the electrical axis; and 4) rapid rotor displacement promoted self-termination by collision with tissue borders, but persistent EADs could regenerate single or multiple focal excitations that reinitiated reentry. These findings may explain many features of Torsades des pointes, such as perpetuation by focal excitations, rapidly changing electrical axis, frequent self-termination, and occasional degeneration to fibrillation.

Nonlinear photodynamic therapy: method of pulsed oxygen depletion.

The photodynamic therapy technique involving pulsed oxygen depletion (POD) in tissue by long high-energy pulses of light was studied theoretically. The possibility of creating a uniform distribution of a therapeutic dose throughout a tumor using both surface and interstitial irradiation is shown. Possible thickness of the treated tissue layer is estimated. The comparison with other methods of nonlinear photodynamic therapy is made.

Nonlinear photodynamic therapy. Photochemical dose levelling within a tumor by saturating a photosensitizer's triplet states.

The photodynamic therapy involving saturation of triplet state of a photosensitizer by short high-energy light pulses was studied theoretically. The possibility of creating a uniform therapeutic dose distribution throughout a large tumor using both surface and interstitial irradiation is shown. Possible thickness of the treated tissue layer and the required duration of the PDT session are estimated.

Intracellular Ca dynamics in ventricular fibrillation.

In the heart, membrane voltage (Vm) and intracellular Ca (Cai) are bidirectionally coupled, so that ionic membrane currents regulate Cai cycling and Cai affects ionic currents regulating action potential duration (APD). Although Cai reliably and consistently tracks Vm at normal heart rates, it is possible that at very rapid rates, sarcoplasmic reticulum Cai cycling may exhibit intrinsic dynamics. Non-voltage-gated Cai release might cause local alternations in APD and refractoriness that influence wavebreak during ventricular fibrillation (VF). In this study, we tested this hypothesis by examining the extent to which Cai is associated with Vm during VF. Cai transients were mapped optically in isolated arterially perfused swine right ventricles using the fluorescent dye rhod 2 AM while intracellular membrane potential was simultaneously recorded either locally with a microelectrode (5 preparations) or globally with the voltage-sensitive dye RH-237 (5 preparations). Mutual information (MI) is a quantitative statistical measure of the extent to which knowledge of one variable (Vm) predicts the value of a second variable (Cai). MI was high during pacing and ventricular tachycardia (VT; 1.13 +/- 0.21 and 1.69 +/- 0.18, respectively) but fell dramatically during VF (0.28 +/- 0.06, P < 0.001). Cai at sites 4-6 mm apart also showed decreased MI during VF (0.63 +/- 0.13) compared with pacing (1.59 +/- 0.34, P < 0.001) or VT (2.05 +/- 0.67, P < 0.001). Spatially, Cai waves usually bore no relationship to membrane depolarization waves during nonreentrant fractionated waves typical of VF, whereas they tracked each other closely during pacing and VT. The dominant frequencies of Vm and Cai signals analyzed by fast Fourier transform were similar during VT but differed significantly during VF. Cai is closely associated with Vm closely during pacing and VT but not during VF. These findings suggest that during VF, non-voltage-gated Cai release events occur and may influence wavebreak by altering Vm and APD locally.

Intracellular calcium cycling, early afterdepolarizations, and reentry in simulated long QT syndrome.

OBJECTIVES: The purpose of this study was to investigate interactions between early afterdepolarizations (EADs) and reentry in long QT (LQT) syndromes. BACKGROUND: EADs, a characteristic feature of congenital and acquired LQT syndromes, are classically bradycardia dependent. Mechanisms by which they promote tachyarrhythmias such as torsades de pointes and ventricular fibrillation are not fully understood. Recent evidence suggests that EADs also may occur at rapid heart rates as a sequela of spontaneous sarcoplasmic reticulum (SR) Ca(2+) release related to intracellular Ca(2+) overload. Here, we performed computer simulations to explore the arrhythmogenic consequences of this phenomenon. METHODS: We used a modified version of the Luo-Rudy dynamic model in one-dimensional and two-dimensional cardiac tissue with the time-dependent K(+) currents I(Kr) or I(Ks) reduced by 50% to simulate acquired and congenital LQT syndromes. RESULTS: (1) Spontaneous SR Ca(2+) release prolonged action potential duration but did not induce overt EADs unless K(+) current density was reduced to simulate acquired and congenital LQT syndromes. (2) In simulated LQT syndromes, EADs were capable of both terminating and reinitiating one-dimensional reentry. (3) A similar phenomenon in simulated 2D tissue led to reinitiation of spiral wave reentry that otherwise would have self-terminated. (4) Reentry reinitiation occurred only when the L-type Ca(2+) current and SR Ca(i) cycling were potentiated to simulate moderate sympathetic stimulation, consistent with the known arrhythmogenic effects of sympathetic activation (and protection by beta-blockers) in LQT syndromes. CONCLUSIONS: These computer simulations suggest that EADs related to spontaneous SR Ca(2+) release can enhance arrhythmogenesis in LQT syndromes by reinitiating reentry.

Nonlinear photodynamic therapy. Saturation of a photochemical dose by photosensitizer bleaching.

Photodynamic therapy with total photobleaching of a photosensitizer was studied theoretically. The possibilities of having constant therapeutic dose within a large extent of a tissue and even of obtaining the maximal dose at a particular depth were considered. The use of both surface irradiation or interstitial irradiation were evaluated.