Beyond the microcirculation: sequestration of infected red blood cells and reduced flow in large draining veins in experimental cerebral malaria.

Sequestration of infected red blood cells (iRBCs) in the microcirculation is a hallmark of cerebral malaria (CM) in post-mortem human brains. It remains controversial how this might be linked to the different disease manifestations, in particular brain swelling leading to brain herniation and death. The main hypotheses focus on iRBC-triggered inflammation and mechanical obstruction of blood flow. Here, we test these hypotheses using murine models of experimental CM (ECM), SPECT-imaging of radiolabeled iRBCs and cerebral perfusion, MR-angiography, q-PCR, and immunohistochemistry. We show that iRBC accumulation and reduced flow precede inflammation. Unexpectedly, we find that iRBCs accumulate not only in the microcirculation but also in large draining veins and sinuses, particularly at the rostral confluence. We identify two parallel venous streams from the superior sagittal sinus that open into the rostral rhinal veins and are partially connected to infected skull bone marrow. The flow in these vessels is reduced early, and the spatial patterns of pathology correspond to venous drainage territories. Our data suggest that venous efflux reductions downstream of the microcirculation are causally linked to ECM pathology, and that the different spatiotemporal patterns of edema development in mice and humans could be related to anatomical differences in venous anatomy.

Energy yield analysis of textured perovskite silicon tandem solar cells and modules.

Perovskite silicon tandem solar cells combine potentially low production costs with the ability to surpass the efficiency limit of silicon single junction solar cells. Optical modeling and optimization are crucial to achieve this ambitious goal in the near future. The optimization should seek to maximize the energy yield based on realistic environmental conditions. This work analyzes the energy yield of perovskite silicon tandem solar cells and modules based on realistic experimental data, with a special focus on the investigation of surface textures at the front and rear side of the solar cell and its implication for reflection as well as parasitic absorption properties. The investigation reveals a 7.3%rel higher energy yield for an encapsulated tandem cell with a textured front side compared with an encapsulated high efficiency single junction solar cell with 24.3% harvesting efficiency for irradiance data of the year 2014 in Freiburg/Germany.

Comparing brain activity patterns during spontaneous exploratory and cue-instructed learning using single photon-emission computed tomography (SPECT) imaging of regional cerebral blood flow in freely behaving rats.

Learning can be categorized into cue-instructed and spontaneous learning types; however, so far, there is no detailed comparative analysis of specific brain pathways involved in these learning types. The aim of this study was to compare brain activity patterns during these learning tasks using the in vivo imaging technique of single photon-emission computed tomography (SPECT) of regional cerebral blood flow (rCBF). During spontaneous exploratory learning, higher levels of rCBF compared to cue-instructed learning were observed in motor control regions, including specific subregions of the motor cortex and the striatum, as well as in regions of sensory pathways including olfactory, somatosensory, and visual modalities. In addition, elevated activity was found in limbic areas, including specific subregions of the hippocampal formation, the amygdala, and the insula. The main difference between the two learning paradigms analyzed in this study was the higher rCBF observed in prefrontal cortical regions during cue-instructed learning when compared to spontaneous learning. Higher rCBF during cue-instructed learning was also observed in the anterior insular cortex and in limbic areas, including the ectorhinal and entorhinal cortexes, subregions of the hippocampus, subnuclei of the amygdala, and the septum. Many of the rCBF changes showed hemispheric lateralization. Taken together, our study is the first to compare partly lateralized brain activity patterns during two different types of learning.

Fox urine exposure induces avoidance behavior in rats and activates the amygdalar olfactory cortex.

Predator odors represent a group of biologically-relevant chemosignals called kairomones. Kairomones enable prey animals to recognize potential predatory threats in their environment and to initiate appropriate defensive responses. Although the behavioral repertoire of anti-predatory responses (e.g. avoidance, freezing, risk assessment) has been investigated extensively, our knowledge about the neural network mediating these innate fear responses is rather limited. In the present study, the GABAA agonist muscimol was bilaterally injected (2.6 nmol/0.3 µl) into the amygdalar olfactory cortex (AOC), a brain area that receives massive olfactory input from both olfactory systems and is strongly interconnected with the medial hypothalamic defense circuit. Temporary inactivation of the AOC substantially disrupted avoidance behavior of rats to fox urine that is strongly avoided under control conditions (saline injections). Taken together, these results demonstrate that the AOC is critically involved in fox urine-induced fear behavior. This suggests that the AOC is part of a brain fear circuit that mediates innate fear responses toward predatory odors.

Disrupted cross-laminar cortical processing in ß amyloid pathology precedes cell death.

Disruption of neuronal networks in the Alzheimer-afflicted brain is increasingly recognized as a key correlate of cognitive and memory decline in Alzheimer patients. We hypothesized that functional synaptic disconnections within cortical columnar microcircuits by pathological ß-amyloid accumulation, rather than cell death, initially causes the cognitive impairments. During development of cortical ß-amyloidosis with still few plaques in the transgenic 5xFAD mouse model single cell resolution mapping of neuronal thallium uptake revealed that electrical activity of pyramidal cells breaks down throughout infragranular cortical layer V long before cell death occurs. Treatment of 5xFAD mice with the glutaminyl cyclase inhibitor, PQ 529, partially prevented the decline of pyramidal cell activity, indicating pyroglutamate-modified forms, potentially mixed oligomers of Aß are contributing to neuronal impairment. Laminar investigation of cortical circuit dysfunction with current source density analysis identified an early loss of excitatory synaptic input in infragranular layers, linked to pathological recurrent activations in supragranular layers. This specific disruption of normal cross-laminar cortical processing coincided with a decline of contextual fear learning.

Tumor cell uptake of 99mTc-labeled 1-thio-ß-D-glucose and 5-thio-D-glucose in comparison with 2-deoxy-2-[18F]fluoro-D-glucose in vitro: kinetics, dependencies, blockage and cell compartment of accumulation.

PURPOSE: This study was conducted to investigate the capacity of (99m)Tc-labeled 1-thio-ß-D-glucose ((99m)Tc-1-TG) and 5-thio-D-glucose ((99m)Tc-5-TG) to act as a marker for glucose metabolism in tumor cells in vitro. PROCEDURES: We investigated the cellular uptake of (99m)Tc-1-TG, (99m)Tc-5-TG, and 2-deoxy-2-[(18)F]fluoro-D-glucose((18)F-FDG) in a human colorectal carcinoma and human lung adenocarcinoma cell line (HCT-116, A549) at different time points and varying glucose/insulin concentrations and under transporter blockage by cytochalasin-B and phloretin. Cell compartment analysis was performed. RESULTS: A significant uptake and time dependency thereof, a significant uptake dependency on glucose and insulin and a significant uptake inhibition by cytochalasin-B for (99m)Tc-1-TG and (99m)Tc-5-TG, was shown. Albeit substantial, the uptake was less pronounced in (99m)Tc-1-TG and (99m)Tc-5-TG compared with (18)F-FDG. (99m)Tc-1-TG and (99m)Tc-5-TG showed a higher accumulation in the cell membranes compared with (18)F-FDG. CONCLUSION: Tc-1-TG and (99m)Tc-5-TG showed an uptake in vitro with glucose analog characteristics but with membranous accumulation. Tumor imaging should be investigated in an animal model.

Prostaglandin E2 secretion from gingival fibroblasts treated with interleukin-1beta: effects of lipid extracts from Porphyromonas gingivalis or calculus.

Complex lipids of Porphyromonas gingivalis have been identified in lipid extracts from calculus-contaminated root surfaces and in diseased gingival tissues. However, little is known about the biological effects of these complex lipids on host cells. The purpose of this study was to evaluate the effects of P. gingivalis or calculus lipids on prostaglandin secretion from gingival fibroblasts. Lipids were extracted from paired subgingival plaque and teeth samples, and calculus-contaminated root surfaces before and after scaling and root planing, in order to determine the relevant levels of lipid extracts for the treatment of gingival fibroblasts in culture. Primary cultures of gingival fibroblasts were exposed to lipid extracts from either P. gingivalis or calculus/teeth for a period of 7 days. Control and lipid-treated cultures were exposed to human recombinant interleukin-1beta for 48 h and prostaglandin secretion from interleukin-1beta-treated fibroblasts was compared with control and lipid-treated fibroblasts without interleukin-1beta treatment. These experiments demonstrated that P. gingivalis lipids or calculus-tooth lipids potentiate interleukin-1beta-mediated prostaglandin secretory responses from gingival fibroblasts. Additionally, P. gingivalis or calculus-tooth lipid extracts were readily taken up by gingival fibroblasts as measured by bacterial fatty acid recovery in lipid extracts of cultured fibroblasts. These results indicate that bacterial lipid penetration into gingival tissues in combination with a chronic inflammatory response may substantially potentiate prostaglandin secretion from gingival fibroblasts, thereby promoting tissue destructive processes associated with adult periodontitis.

Interleukin-6 and the soluble interleukin-6 receptor induce stem cell factor and Flt-3L expression in vivo and in vitro.

OBJECTIVE: We recently established transgenic animals expressing either interleukin-6 (IL-6) or the soluble IL-6 receptor (sIL-6R) alone, or both components, IL-6 and the sIL-6R, in the liver. This animal model demonstrated that the expression of IL-6 in combination with its sIL-6R led to extramedullary expansion of hematopoietic progenitor cells in the spleen and liver. MATERIALS AND METHODS: We studied other relevant hematopoietic cytokines involved in the IL-6/sIL-6R-induced stimulation of hematopoiesis. RESULTS: Using immunohistochemistry, we showed that cell-associated stem cell factor (SCF) and Flt-3L expression were upregulated in liver and spleen only in double transgenic mice but not in IL-6 or sIL-6R single transgenic animals. Moreover, on murine NIH/3T3 fibroblasts and on human primary forskin fibroblasts, stimulation with the IL-6/sIL-6R complex, and to a lesser extent with IL-6 alone, led to induction of cellular SCF and Flt-3L expression. When human HTB-158 fibroblasts were stimulated with the IL-6/sIL-6R complex and subsequently cocultured with human umbilical cord CD34(+) cells, a significant upregulation in colony growth was found. CONCLUSIONS: We showed that IL-6 in combination with its soluble receptor stimulates cellular SCF and Flt-3L expression in vivo and in vitro. Cellular upregulation of SCF and Flt-3L by IL-6/sIL-6R might be used for the development of new stroma cell systems for ex vivo expansion of hematopoietic progenitor cells.

Leiomyosarcoma presenting as a mandibular gingival swelling: a case report.

We report a case of primary low-grade leiomyosarcoma of the mandible in an otherwise healthy young woman. The neoplasm presented as a painful, pericoronal gingival swelling that mimicked an acute periodontal infection. It was managed accordingly, with curettage, debridement, and antibiotics. When the lesion failed to respond to this treatment approach, a biopsy was performed. Microscopy revealed a malignant mesenchymal neoplasm which, on immunohistochemistry analysis, demonstrated reactivity for smooth muscle actin (SMA) and vimentin. This established the diagnosis of leiomyosarcoma; subsequently, an en bloc resection of mandibular bone and overlying soft tissue was performed. Close follow-up for over 10 years has revealed no evidence of recurrent or metastatic disease. Since the patient was taking oral contraceptives prior to the onset of the lesion, a possible link between estrogen and smooth muscle tumors is considered.

The effect of lowered extracellular Na+ concentration on ultraviolet light-induced relaxation of vasoconstricted rabbit isolated thoracic aorta.

The effect of lowering extracellular ion concentration on ultraviolet (UV) light-induced photorelaxation of norepinephrine(NE)-constricted rabbit isolated thoracic aorta was investigated. The magnitude of the photorelaxation response (similar to acetylcholine-induced, but not nitroprusside-induced, relaxation) progressively declined, in the absence of an effect on NE-induced vasoconstriction, as the total extracellular ion concentration was progressively reduced. This diminution in the photorelaxation response was duplicated by isosmotic lowering of the extracellular concentration of Na+, but not other ions, from 145 to 25 mM and was not restored by the replenishment of the Na+ deficiency by equimolar amounts of mannitol or Li+. In contrast, choline fully substituted for Na+. These findings suggest a fundamental difference in the ion dependency (and, hence, the mechanisms) of UV-induced photorelaxation and the vasorelaxations induced by acetylcholine or sodium nitroprusside.

Pharmacological evidence that captopril possesses an endothelium-mediated component of vasodilation: effect of sulfhydryl groups on endothelium-derived relaxing factor.

Captopril, an angiotensin-converting enzyme inhibitor, reportedly can scavenge superoxide anion (O2-), a property attributed to its sulfhydryl group. The present investigation, using rabbit aortic rings precontracted with either norepinephrine or clonidine, was designed to determine whether captopril possesses an endothelium-dependent component of vasodilation related to its ability to protect endothelium-derived relaxing factor (EDRF) from superoxide-mediated destruction. Also studied were enalaprilat, a nonsulfhydryl angiotensin-converting enzyme-inhibitor, superoxide dismutase, and the sulfhydryl compounds glutathione (GSH), N-2-mercaptopropionylglycine (MPG) and N-acetylcysteine (NAC). Captopril, but not enalaprilat, caused dose-dependent relaxations in preconstricted aortic rings containing an intact endothelium. Rings denuded of endothelium were unresponsive to any dose of captopril. Captopril's vasodilation was not related to prostaglandin influence but was associated with an increase in cyclic GMP. Superoxide dismutase, GSH, MPG and NAC also produced endothelium-dependent relaxations similar to captopril. It was also demonstrated that endothelium-dependent relaxations to acetylcholine were enhanced by captopril, GSH, MPG and NAC but not by enalaprilat. In another set of experiments, the ability of captopril to inhibit superoxide-mediated inactivation of EDRF was examined. Pyrogallol, a potent generator of O2-, and superoxide dismutase, a scavenger of O2-, were used as a basis for comparing a possible scavenging effect of captopril. In preconstricted rings, pyrogallol elicited endothelium-dependent contractions that were attenuated by both captopril and superoxide dismutase. Similar effects were found with GSH, MPG and NAC but not with enalaprilat. These results suggest that captopril's endothelium-dependent vasodilation is due to its sulfhydryl group and the ability of the latter to scavenge O2-, thereby protecting EDRF.

Congenital malformations in babies of diabetic mothers.

In 1979-80 a national survey of the incidence of congenital malformations in babies born to diabetic mothers in the United Kingdom was carried out by questionnaire. Of the 1034 mothers reported, 773 were known to have diabetes before the index pregnancy. The incidence of congenital malformations ws 7.1% which is significantly higher than the 2.1% in the offspring reported to the Office of Population, Censuses and Surveys (OPCS) for England and Wales in 1979-80. The increase was most pronounced for malformations of the heart, spine, lungs, and brain. In 40% of the diabetic mothers blood glucose was not recorded during the first trimester of pregnancy, and in this group the malformation rate was twice that in babies born of mothers who had had at least one reported blood glucose estimation during this time. We conclude that there is an urgent need to improve health education and supervision before and during pregnancy in all diabetic women if the prevalence of malformations amongst their offspring is to be reduced.

The UK diabetic pregnancy survey.

A prospective, national survey of the UK which examined the management and outcome of pregnancy complicated by maternal diabetes is described. The perinatal mortality rate was 3.7 and 1.5 times greater than the overall UK rate and the malformation rate 6.4% and 1.9% in pregnancies where the mother had insulin-dependent and gestational diabetes respectively. In 57% of cases no blood glucose measurement was recorded in the first trimester of pregnancy. Significantly fewer malformed infants resulted from pregnancies where a first trimester blood glucose was recorded, irrespective of the value. Second and third trimester blood glucose values did not predict malformation but correlated inversely with gestational age at delivery and this was the major factor predicting the outcome of pregnancy.

Antigenic modulation in retinoblastoma: a flow cytometric study.

Flow cytometry (FCM) was used to investigate antigenic expression and modulation during the cell cycle of Y-79 and WERI-Rb1 tissue cultured retinoblastoma cell lines using a polyclonal anti-Y-79 antibody and fluorescein conjugated lectins. Several Y-79 resting cell populations were identified by FCM analysis of antibody binding, while only a single population with uniform antigen expression was found to exist in the synthetic and mitotic phases. WERI-Rb1 cells bound antibody approximately equally in each phase of the cell cycle. Multiple cell populations with different lectin binding affinities were seen in the resting phase with FITC-concanavalin A, FITC-ricinus communis-60 and FITC-ricinus communis-120 (FITC-RCA-120). During the S-phase of the cell cycle, a higher percentage of cells bound FITC-RCA-120 and FITC wheat germ agglutinin. The relationship between antigenic expression during the cell cycle and treatment considerations in retinoblastoma is discussed.

Teichoic acids of Streptococcus agalactiae: chemistry, cytotoxicity, and effect on bacterial adherence to human cells in tissue culture.

The ratio of teichoic acid to lipoteichoic acid (LTA) in a strain of Streptococcus agalactiae type III was found to be 8:1, with the total amount of LTA being 0.1% of the dry weight of the organism. Purified teichoic acid contained D-alanine and possibly a small amount of D-glucose and was approximately 22 glycerol phosphate units in length. The linkage between each of these units was 1-3. In addition, LTA contained a complex lipid, more glucose, and an unusually high content of a short-chain fatty acid, tridecanoic acid. This LTA was cytotoxic for a variety of human cell monolayers in tissue culture, including one derived from the human central nervous system. Established human cells were more sensitive than primary cell monolayers to this LTA, with as little as 12.5 micrograms of LTA per ml being cytotoxic for HeLa cells. Teichoic acid (250 micrograms/ml) was nontoxic under identical conditions. These cytotoxicity results suggest an LTA involvement in group B streptococcal pathogenesis. Also, the first model system for the study of group B streptococcal adherence to primary human embryonic amnion cells in tissue culture is detailed. This system was used to quantitate pronounced differences in tissue tropism between S. agalactiae and Streptococcus pyogenes and showed enhanced binding by this group A coccus over that of S. agalactiae for amnion cell monolayers. The adherence of both streptococcal species to only a portion (40%) of these amnion cells suggested that host cell receptor expression may vary for primary cells in vitro. Finally, this strain of S. agalactiae was shown to adhere to amnion cells by a non-LTA-mediated mechanism. The possibility of an LTA-mediated versus a protein-mediated adherence mechanism for host cells that is related to the virulence of S. agalactiae is discussed.

A method for evaluating therapy for hay fever. A comparison of four treatments.

This study was undertaken in order to develop a method for comparing the value of different forms of treatment for hay fever. A cross-over trial was carried out in sixty-one patients, comparing four treatments: topical corticosteroids, topical cromoglycates, placebo tablets and oxatomide (a new oral treatment with antihistamine and cromoglycate-like properties). Three methods were used to compare these treatments: (1) post-treatment symptom questionnaires; (2) daily analogue line scores of symptoms; and (3) nasal FEV1. Of these, daily analogue line diary scores, with an analysis which took into account variation in pollen count, proved to be the most sensitive. By employing this diary method, it was shown that all three active treatments were significantly better than placebo and that topical corticosteroids were significantly better than topical cromoglycates. The activity of oxatomide was found to be not significantly different from that of steroids or cromoglycate, but it was associated with more frequent side-effects. It is suggested that daily diaries, combining symptom relief and freedom from side effects into a single score of 'usefulness' adjusted for pollen count, are suitable means for comparing treatments for hay fever.

Calcium balance in paraplegic patients: influence of injury duration and ambulation.

Calcium metabolic balance determinations, which have been done in various clinical and experimental conditions, were applied to the study of 8 spinal cord injured patients receiving a diet with 1600 mg calcium and 85 to 120 gm protein daily. All of the patients had hypercalciuria prior to ambulation. Those with spinal cord injuries of less than 3 months duration (early group) had a calcium balance of -27 mg before ambulation and 235 mg after ambulation. Patients with spinal cord injuries of 6 months or more duration (late group) had calcium balances of 55 mg before ambulation and 175 mg after ambulation. Ambulation significantly decreased the hypercalciuria and modified the calcium balance in a positive direction. Smaller changes were noted in the responses of the late group than in those of the early group. Early ambulation will probably prevent bone loss, calcium stones in the genitourinary tract, and other sequellae of negative calcium balance.

[New therapeutic measures for the treatment of ulcers]. / Nouvelles ressources thérapeutiques dans le traitement des ulcères.

In this study we tested the effect of vibrating electromagnetic waves on both arterial and varicose ulcers. The two transmitters we used were the diatrom and the fel, which differ in the energy transmitted and the means of application (direct contact electrode for the fel, distance transmission for the diatrom). Out of 17 cases treated we obtained 15 cures. This proportion of positive results encountered in traumatology and in dermatology for cases where the vascular factor played an important role, makes it possible to consider the application of vibrating electromagnetic waves as a valid therapy for ulcers.