Artificial and natural interventions for chemotherapy- and / or radiotherapy-induced cognitive impairment: A systematic review of animal studies.

BACKGROUND: Cancer survivors frequently experience cognitive impairments. This systematic review assessed animal literature to identify artificial (pharmaceutical) or natural interventions (plant/endogenously-derived) to reduce treatment-related cognitive impairments. METHODS: PubMed, EMBASE, PsycINFO, Web of Science, and Scopus were searched and SYRCLE's tool was used for risk of bias assessment of the 134 included articles. RESULTS: High variability was observed and risk of bias analysis showed overall poor quality of reporting. Results generally showed positive effects in the intervention group versus cancer-therapy only group (67% of 156 cognitive measures), with only 15 (7%) measures reporting cognitive impairment despite intervention. Both artificial (61%) and natural (75%) interventions prevented cognitive impairment. Artificial interventions involving GSK3B inhibitors, PLX5622, and NMDA receptor antagonists, and natural interventions utilizing melatonin, curcumin, and N-acetylcysteine, showed most consistent outcomes. CONCLUSIONS: Both artificial and natural interventions may prevent cognitive impairment in rodents, which merit consideration in future clinical trials. Greater consistency in design is needed to enhance the generalizability across studies, including timing of cognitive tests and description of treatments and interventions.

Unveiling bulk and surface radiation forces in a dielectric liquid.

Precise control over light-matter interactions is critical for many optical manipulation and material characterization methodologies, further playing a paramount role in a host of nanotechnology applications. Nonetheless, the fundamental aspects of interactions between electromagnetic fields and matter have yet to be established unequivocally in terms of an electromagnetic momentum density. Here, we use tightly focused pulsed laser beams to detect bulk and boundary optical forces in a dielectric fluid. From the optical convoluted signal, we decouple thermal and nonlinear optical effects from the radiation forces using a theoretical interpretation based on the Microscopic Ampère force density. It is shown, for the first time, that the time-dependent pressure distribution within the fluid chiefly originates from the electrostriction effects. Our results shed light on the contribution of optical forces to the surface displacements observed at the dielectric air-water interfaces, thus shedding light on the long-standing controversy surrounding the basic definition of electromagnetic momentum density in matter.

Longitudinal associations between exposure to anesthesia and neurocognitive functioning in pediatric medulloblastoma.

AIM: To examine whether anesthesia exposure is associated with neurocognitive decline in pediatric medulloblastoma. METHODS: Patients were treated at St. Jude Children's Research Hospital and completed ≥2 protocol-directed neurocognitive assessments (n = 107) as part of a multisite clinical trial for pediatric medulloblastoma (NCT00085202). Patients received risk-adapted craniospinal photon irradiation, followed by four cycles of high-dose chemotherapy and stem cell rescue. Neurocognitive testing was completed at study baseline (after surgery and <2 weeks of starting radiation therapy) and annually for 5 years. Data on anesthesia exposure during treatment was abstracted from medical records. RESULTS: Patients were 10.2 years at diagnosis on average (SD = 4.5; 37% female, 73% average-risk). Mean cumulative anesthesia duration was 20.4 h (SD = 15.2; range 0.7-55.6 h). In the overall group, longer anesthesia duration was associated with greater declines in IQ (Estimate = -0.08, P < 0.001), attention (Estimate = -0.10, P < .001) and processing speed (Estimate = -0.13, P < 0.001). Similar results were shown in subgroups of patients who were <7 years at diagnosis (IQ = -0.14, P = 0.027; Attention = -0.25: P = 0.011), ≥7 years at diagnosis (Attention = -0.07, P = 0.039; Processing Speed = -0.08, P = 0.022), treated for high-risk disease (IQ = -0.09, P = 0.024; Attention = -0.11, P = 0.034; Processing Speed = -0.13, P = 0.001), or treated for average-risk disease (IQ = -0.05, P = .022; Attention = -0.08, P = 0.011; Processing Speed = -0.10, P < 0.001). CONCLUSION: Greater anesthesia exposure is a risk factor for clinically significant neurocognitive decline, in addition to factors of age at diagnosis and treatment risk arm. This result is notable as there are evidence-based strategies that can limit the need for anesthesia. Limiting anesthesia exposure, as feasible, may mitigate neurocognitive late effects, and thus, improve quality of life for survivors.

Bolometer operating at the threshold for circuit quantum electrodynamics.

Radiation sensors based on the heating effect of absorbed radiation are typically simple to operate and flexible in terms of input frequency, so they are widely used in gas detection1, security2, terahertz imaging3, astrophysical observations4 and medical applications5. Several important applications are currently emerging from quantum technology and especially from electrical circuits that behave quantum mechanically, that is, circuit quantum electrodynamics6. This field has given rise to single-photon microwave detectors7-9 and a quantum computer that is superior to classical supercomputers for certain tasks10. Thermal sensors hold potential for enhancing such devices because they do not add quantum noise and they are smaller, simpler and consume about six orders of magnitude less power than the frequently used travelling-wave parametric amplifiers11. However, despite great progress in the speed12 and noise levels13 of thermal sensors, no bolometer has previously met the threshold for circuit quantum electrodynamics, which lies at a time constant of a few hundred nanoseconds and a simultaneous energy resolution of the order of 10h gigahertz (where h is the Planck constant). Here we experimentally demonstrate a bolometer that operates at this threshold, with a noise-equivalent power of 30 zeptowatts per square-root hertz, comparable to the lowest value reported so far13, at a thermal time constant two orders of magnitude shorter, at 500 nanoseconds. Both of these values are measured directly on the same device, giving an accurate estimation of 30h gigahertz for the calorimetric energy resolution. These improvements stem from the use of a graphene monolayer with extremely low specific heat14 as the active material. The minimum observed time constant of 200 nanoseconds is well below the dephasing times of roughly 100 microseconds reported for superconducting qubits15 and matches the timescales of currently used readout schemes16,17, thus enabling circuit quantum electrodynamics applications for bolometers.

Flux-tunable heat sink for quantum electric circuits.

Superconducting microwave circuits show great potential for practical quantum technological applications such as quantum information processing. However, fast and on-demand initialization of the quantum degrees of freedom in these devices remains a challenge. Here, we experimentally implement a tunable heat sink that is potentially suitable for the initialization of superconducting qubits. Our device consists of two coupled resonators. The first resonator has a high quality factor and a fixed frequency whereas the second resonator is designed to have a low quality factor and a tunable resonance frequency. We engineer the low quality factor using an on-chip resistor and the frequency tunability using a superconducting quantum interference device. When the two resonators are in resonance, the photons in the high-quality resonator can be efficiently dissipated. We show that the corresponding loaded quality factor can be tuned from above 105 down to a few thousand at 10 GHz in good quantitative agreement with our theoretical model.

Chiral imaging of collagen by second-harmonic generation circular dichroism.

We provide evidence that the chirality of collagen can give rise to strong second-harmonic generation circular dichroism (SHG-CD) responses in nonlinear microscopy. Although chirality is an intrinsic structural property of collagen, most of the previous studies ignore that property. We demonstrate chiral imaging of individual collagen fibers by using a laser scanning microscope and type-I collagen from pig ligaments. 100% contrast level of SHG-CD is achieved with sub-micrometer spatial resolution. As a new contrast mechanism for imaging chiral structures in bio-tissues, this technique provides information about collagen morphology and three-dimensional orientation of collagen molecules.

Characterization of cell-specific modulatory element in the murine ornithine decarboxylase promoter.

The promoter of the murine ornithine decarboxylase (ODC) gene contains, adjacent to the TATA box, a cAMP response element (CRE)-like motif that interacts with specific nuclear proteins. Here we examine the role of this CRE-like element (CREL) in ODC promoter activation in proliferating cells. Mutations that abolished binding of nuclear proteins to CREL influenced only marginally the cAMP induction of the reporter constructs driven by 1.6 kb of the ODC promoter. Instead, these mutations altered the basal promoter function in a cell-specific manner, in that they reduced the promoter activity in CV-1 cells, but increased it in NIH/3T3, CHO and HeLa cells. Thus, depending on the cell type, the CREL motif is able to confer either repression or activation on ODC gene transcription. In contrast with 1.6 kb promoter constructs, the same mutations in the context of a shorter sequence (proximal 133 nt) reduced the promoter strength in all cell types studied. The ability of the CREL element to attenuate transcription seems to be connected with the function of some upstream regulatory elements. Differences in nuclear proteins binding to CREL, as studied by electrophoretic mobility shift assays (EMSAs), did not explain the findings on cell-type specificity in transcriptional activation, as mutations in CREL abrogated formation of specific CREL-protein complexes in all cell lines examined. The protein complexes interacting with CREL were not recognized by antibodies specific for CRE-binding proteins CREB-1 and CREB-2, or activating transcription factors ATF-1, ATF-2 and ATF-3. EMSA experiments also demonstrated co-operative interactions between the CREL motif-binding proteins and other nuclear proteins, such as Sp1, interacting with CG-rich sequences of the promoter. In conclusion, the proximal ODC promoter contains a well-conserved regulatory element, which is clearly different from the CRE/ATF element. This motif acts in concert with other distal and proximal elements in a complex cell-specific manner.

Polychlorinated dibenzo-p-dioxins and dibenzofurans via mother's milk may cause developmental defects in the child's teeth.

Previous studies have shown developmental dental defects in rhesus macaques and rats experimentally exposed to dioxin. Now it was investigated if dioxin exposure from mother's milk in a normal breast-fed child population correlated with enamel hypomineralization of teeth that mineralize during the first 2 years of life. We studied 102 6-7-year-old Finnish children breast-fed for an average of 10.5 months. Milk samples were collected when the child was 4 weeks old. The concentrations of 17 most toxic polychlorinated dibenzo-p-dioxin and furan congeners were determined. The total exposure to dioxins was calculated from the concentrations in milk and the duration of breast feeding. Hypomineralization of the target teeth was found in 17 children. Both the frequency and severity of the lesions correlated with the total exposure. The results suggest that at the prevailing levels in human milk, dioxin may be an important cause of hypomineralization in the developing teeth of children.

Analyses of the Drosophila quit, ovarian tumor and shut down mutants in oocyte differentiation using in situ hybridisation.

We have studied the role of three loci, quit, ovarian tumor and shut down during oocyte differentiation in Drosophila by using in situ hybridisation and double mutant analyses. Mutations in qui and otu disturb the cystocyte divisions and the oocyte determination, while mutations in shu affect the cystocyte integrity, nevertheless allowing differentiation of normal-looking egg chambers with an oocyte. In all mutants the transport of molecules towards the posterior end of the egg chamber takes place as revealed by the accumulation of Bic-D or K10 transcripts. We show that the transport is ineffective in the qui and otu mutants apparently due to the lack of a properly differentiated oocyte. In the shu mutant the transport collapses and the oocyte is lost, leading to egg chambers with 15 nurse cells. We also show that one function of qui+ is to enhance otu+ mRNA expression, suggesting that these genes control the cystocyte maturation via the same pathway.

Phenotypes of conjunctival inflammatory cells in sarcoidosis.

Phenotypes of the infiltrating mononuclear cells of the lower fornix conjunctiva of nine patients with sarcoidosis and six controls were studied using monoclonal antibodies and a modified immunoperoxidase method. Four patients had sarcoidosis of recent onset (duration of 2 years or less) and five patients had a chronic disease (duration of 3 or more years). The inflammatory cells in the sarcoid conjunctival specimens were predominantly T lymphocytes, the vast majority of which were of T helper/inducer subtype expressing Leu-3a + 3b positivity. The ratio of T helper/inducer cells to T suppressor/cytotoxic cells was 3.9 on average but only 0.9 in controls. Epithelioid cell granulomas were seen in three specimens in one case of recent onset and in two chronic cases comprising a marked amount (more than 15 cells/visual field) of cells bearing phenotypes of macrophages, T cells, T helper/inducer cells and HLA-DR antigen, and in smaller quantities of T suppressor/cytotoxic cells. The mean number of all immunocompetent cell subtypes of specimens from newly diagnosed patients exceeded that of specimens from chronic patients. We believe that the sarcoid immune reaction in the conjunctiva is a dynamic process in which proliferation of immunocompetent mononuclear cells precedes the stage of granuloma formation.

Histochemical demonstration of adrenergic nerves in the stroma of human cornea.

Both fetal and adult human corneas were subjected to a variety of histochemical techniques for the demonstration of catecholamines. The techniques included both sodium-potassium-glyoxylic acid-induced fluorescence (SPG) and formaldehyde-induced fluorescence after freeze-drying (FIF) procedure. In fetal corneas the presence of adrenergic nerve fibers could be demonstrated by both SPG and FIF techniques. In contrast, in adult human corneas the adrenergic nerves could be identified only with the SPG technique, whereas with FIF the identification of specific catecholamine fluoresence was not possible due to extensive collagen autofluorescence.

[O'Connor's surgical method in abducens nerve paralysis]. / O'Connors Operationsmethode bei Abducens-Paralyse.

Eighteen patients who underwent surgery for nervus abducens paresis (NAP), were kept under observation for up to 23 years after the operation. Three patients had paresis of both nerves. The operation, employing O'Connor's method (11 patients) included the grafting of split inferior and superior rectus muscles on to the insertion of the resected lateral rectus muscle. Six patients underwent resection and retroposition of the lateral and medial rectus muscles respectively. O'Connor's method produced functionally and cosmetically better results than surgery on horizontal muscles in congenital NAP (13 patients). In NAP due to organic damage (e.g., trauma) (5 patients) the results obtained with the two methods were similar.

Electron microscopic study on the innervation of the human lower respiratory tract: evidence of adrenergic nerves.

Samples of human lung were studied electron microscopically after fixation with glutaraldehyde and osmium tetroxide. Three different types of nerve profiles were found in the human lower respiratory tract. Type I nerve profiles contained small agranular vesicles 30-50 nm and large granular vesicles ranging from 60 nm to 210 nm. Type II nerve profiles contained small granular vesicles 30-50 nm and a few large granular vesicles ranging from 60 to 120 nm. Type III nerve profiles contained predominantly large irregular vesicles ranging from 60 to 210 nm, and only a few small agranular vesicles. The present electron microscopic results indicate that the smooth muscle layer of human bronchial tree receives adrenergic nerves.

Immunohistochemical localization of neurotensin in hamster adrenal medulla.

Neurotensin-like immunoreactivity was localized in nerve fibers and terminals of hamster adrenal medulla at light and electron microscopy using the peroxidase-antiperoxidase method. Numerous varicose neurotensin-immunoreactive nerves and terminals were found among nonlabeled cell groups situated peripherally in the adrenal medulla. Combined formaldehyde-glutaraldehyde (Faglu) fluorescence and immunohistochemistry of the same vibratome section showed that only norepinephrine cells were innervated by neurotensin-immunoreactive nerves. All norepinephrine cells seemed to be innervated by neurotensin-immunoreactive nerves. Neurotensin-immunoreactive nerves disappeared after extrinsic denervation of the adrenal gland. By electron microscopy numerous neurotensin-immunoreactive terminals were seen to make synaptic contacts with norepinephrine cells and with autonomic ganglion cells present in small numbers among norepinephrine cells. In the terminals neurotensin-like immunoreactivity was localized mainly in large dense-cored vesicles, but some precipitates were also associated with small vesicles, diffusely scattered in the axoplasm. The present findings suggest that in the hamster adrenal medulla part of the nerve terminals arising from splanchnic nerves contain neurotensin-like peptide. The functional significance of these nerves in the hamster adrenal medulla remains to be elucidated.

Indices of neurotransmitter synthesis and release in aging sympathetic nervous system.

Activities of tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH) and choline acetyltransferase (ChAT) were assayed in sympathetic ganglia and adrenal glands of young and aged Fischer-344 rats. The recovery of reserpine-depleted catecholamine stores and catecholamine loss following inhibition of synthesis and intraneuronal degradation also were assessed in sympathetic ganglia of young and aged rats. No age differences were observed in DBH activity of any tissues examined or in the activities of any enzymes in the coeliac-mesenteric ganglion complex. However, TH and ChAT activities were significantly higher in the superior cervical ganglia and adrenal glands of aged rats. In the hypogastric ganglion, only TH activity was higher in the old rats. Recoveries of reserpine-depleted catecholamine stores in the superior cervical and hypogastric ganglia of aged rats were slower than in young rats. Catecholamine loss following inhibition of synthesis and intraneuronal degradation was faster in the superior cervical ganglia but not in the hypogastric ganglia of old rats as compared with young rats. These findings suggest that neurotransmitter synthesis and release are enhanced with age in the superior cervical ganglion. The lack of age-related changes in the hypogastric ganglion might reflect the different cellular composition as well as the physiological role of this ganglion.

VIP like immunoreactive nerves in human respiratory tract. Light and electron microscopic study.

The present study provides light and electron microscopical evidence of Vasoactive Intestinal Peptide - (VIP) like immunoreactive nerves in human lower respiratory tract. Peroxidase antiperoxidase (PAP) technique was used to localize VIP-like immunoreactivity light microscopically and ultrastructurally. Under light microscopy, VIP-like immunoreactive nerves were observed in the smooth muscle layer of secondary bronchi to small bronchioli, and in bronchial glands. In addition, positive immunoreactive nervous network to VIP was found around nerve cell bodies in small microganglia. The bronchial epithelium of airway tract did not receive any VIP positive nerve fibers. Ultrastructurally VIP-like positive immunoreaction was localized in large granular vesicles ranging from 90 to 210 nm. Usually VIP-like positive immunoreactive nerve profiles contained several immunoreactive large vesicles (100-210). However, nerve profiles containing only a few positive large vesicles (80-150) were also observed. Under electron microscopy VIP-positive nerve profiles corresponded ultrastructurally to nerve profiles containing large granular vesicles observed in conventional electronmicroscopy. The present study provides new information about the innervation of human lower airway tract and widens the concept of their functional regulation on the anatomical basis reported here.

The ultrastructure of hypertrophied paraganglia in aged rats.

The catecholamine-storing cells in the paraganglia of old rats showed structural characteristics common to adrenomedullary and paraganglionic cells of young animals. No sign of degeneration was found. Lipofuscin pigment was observed in most cells. The paraganglia were innervated and well supplied by fenestrated sinusoidal capillaries. Their fine structure suggests active endocrine function. An increase in the total bulk of the paraganglia in old rats suggests that they have a physiological role in senescence.

Catecholamine-synthesizing enzymes in paraganglia of aged Fischer-344 rats. Immunohistochemistry and fluorescence microscopy.

The catecholamine-synthesizing enzymes, tyrosine hydroxylase, dopamine-beta-hydroxylase and phenylethanolamine-N-methyltransferase were examined by immunohistochemistry in hypertrophied paraganglia of aged male Fischer-344 rats. All paraganglionic cells reacted with antibodies against tyrosine hydroxylase. Dopamine beta-hydroxylase was identified in most paraganglionic cells, indicating that they synthesized norepinephrine. A variable number of paraganglia were positive for phenylethanolamine-N-methyltransferase, which suggested that they synthesized epinephrine. The formaldehyde-induced fluorescence method demonstrated greenish-yellow fluorescence or yellowish-brown fluorescence. The intensity of the fluorescence was in the same range as in adrenal medullary cells. The observations indicate that paraganglia are capable of synthesizing epinephrine.

Histochemically demonstrable catecholamines in sympathetic ganglia and carotid body of spontaneously hypertensive and normotensive rats.

The catecholamine content and morphology of the superior cervical and the hypogastric ganglion and the carotid body were studied in Spontaneously Hypertensive Rats (SHR) before (at the age of 6 weeks) and after (at the age of 20 weeks) becoming hypertensive, with Wistar Kyoto (WKY) rats as controls. The study was performed by formaldehyde-induced fluorescence method combined with quantitative microfluorimetry of catecholamines. At the age of 6 weeks the only significant difference observed between the rat strains was a greater number of small intensely fluorescent (SIF) cells in the superior cervical ganglion of SHR. At the age of 20 weeks the fluorescence intensity was higher in the principal neurons of the superior cervical ganglion and in glomus cells of the carotid body of SHR compared to WKY. The volumes of superior cervical ganglion and carotid body were larger in 20-week-old SHR compared to WKY. In the hypogastric ganglion differences were not found between SHR and WKY rats. The present results show differences in the superior cervical ganglion and in the carotid body of adult SHR compared to controls. These differences develop during the time period when the SHR become hypertensive, and might be functionally significant in the regulation or maintenance of the increased blood pressure in SHR rats.

The effect of aging on extra-adrenal catecholamine storing cells of the rat.

Cell number and catecholamine histofluorescence were determined in three extra-adrenal chromaffin tissues: the abdominal paraganglia, the carotid body and SIF (small intensely fluorescent)-cells, of male Fischer-344 rats at different ages. Catecholamines were demonstrated using the formaldehyde-induced fluorescence method. The number of paraganglia cells in the retroperitoneal area increased 13.6 fold between 3 and 33 months of age, and the volume of abdominal paraganglia approached 65% of the volume of one adrenal medulla. The emission color of some paraganglia cells shifted from greenish-yellow to yellowish-brown with aging, but differences were not observed in cell number of fluorophore color in the carotid body, a chemoreceptor type of paraganglion. The number of SIF cells (an intraganglionic variant of extra-adrenal chromaffin tissue) in the hypogastric ganglion increased significantly between 3 and 33 months. The pronounced increase of the volume of the paraganglia in aged rats may contribute to elevated concentrations of circulating catecholamines in these animals.