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Regional brain iron level of two patients with haemochromatosis and severe restless Legs syndrome (RLS) were assessed using R2' magnetic resonance imaging (MRI) sequences in both patients and in nine healthy controls. R2' relaxation rates in the patients were decreased in the substantia nigra, red nucleus, and pallidum when compared with the controls. These results indicate that local brain iron deficiency may occur in patients with haemochromatosis and suggest a role for brain iron metabolism in the pathophysiology of RLS. [ABSTRACT FROM AUTHOR]

Given his seminal scientific oeuvre, Joseph P. Weinmann (1896-1960) is considered a pioneer of oral pathology. He also paved the way for generations of scientists and physicians with the standard work "Bone and Bones", his textbook on oral pathology and histology, and the "Oral Pathology Program" at the University of Illinois. Far less well known is the fact that Weinmann, as a Jew, was disenfranchised by the Nazis in Vienna in 1938. Against this background, this study aims to shed light on the circumstances of Weinmann's persecution and subsequent forced emigration, as well as the further development of his career in the United States. This includes the question of which factors were decisive for Weinmann's scientific breakthrough in Chicago. The analysis draws on a variety of archival sources and contemporary printed writings. What at first glance looks like the impressive curriculum vitae of a successful scientist turns out to be a story of loss, violence, and a difficult new beginning. Joseph Weinmann first had to overcome several setbacks - disenfranchisement and expropriation by the National Socialists, a brief imprisonment before his planned escape from Vienna, and a failed immigration attempt in Great Britain - before he succeeded in an international career in the USA, which brought him, among other things, a chair and the presidency of the "American Academy of Oral Pathology". From the results, it can be concluded that Weinmann's success was not due to one specific reason, but based on many mutually beneficial factors (personal relationships, scientific prominence, favorable research environment, fortitude, adaptability, highly sought-after professional specialization)., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

In the following work, sacrificial claddings filled with different brittle materials were investigated, from concrete foam to granular media. They were subjected to blast loading using an explosive driven shock tube, while a sensor measures the load transmission and a high speed camera records the compression of the core. From a macroscopic point of view, concrete foam and granular media can act efficiently as a crushable core but differs greatly in terms of energy dissipation mechanisms. To compare them, granular media was at first treated as a cellular material, and different key parameters (plateau stress, densification strain) were computed using the energy absorption efficiency methodology. The presented tests results, coupled with observation in literature, allow a better understanding on the crushing process of a granular media. In particular, granular media tend to work as a core even for low intensity load, contrary to more classical crushable core.

Harry Sicher (1889-1974), longtime professor at Loyola University Chicago, went down in medical history as a pioneering figure in the area of oral anatomy. His groundbreaking textbook "Oral Anatomy" (1949) was published in numerous languages and editions, becoming the most widely read standard work in its area internationally. This was also true for various other works Sicher authored: orthodontists sought his knowledge about cranial and facial growth, oral surgeons used his pioneering work on anatomy for practicing dental block anesthesia, and his work "Bone and Bones" was read by surgeons and orthopedists. By the end of his life, Sicher had accumulated an array of high-profile awards and honors that brought him a great deal of posthumous fame. One aspect of Sicher's life that remains largely unknown is that the Vienna native was forced to flee the National Socialist regime on account of his Jewish ancestry, which took him to the United States via England. The present article investigates this facet of his life: What were the factors behind Sicher's forced migration? How did this process unfold? Which factors were decisive for allowing him to develop an illustrious career in the United States despite facing adverse conditions? We approach these questions on the basis of comprehensive archival sources and contemporary printed material. What comes to light is that Sicher was forced to overcome significant setbacks before starting anew in the United States. This included his dismissal from the University of Vienna and subsequent dispossession in 1938, a failed attempt to find a position after settling in England in 1938/39, and the painful loss of his mother, who was deported to the Treblinka extermination camp in 1942. After assuming a new position at Loyola University in 1942, Sicher's career in anatomy started an upward path of ever-increasing success. Four factors proved to be decisive in this development: Sicher's strong motivation to learn, his exceptional teaching skills, the unique qualities of his research, and the dense academic network that he was able to connect with, which included other representatives of the "Vienna School"., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Systems emitting ultra-wideband high power microwave (HP/UWB) pulses are developed for military and civilian applications. HP/UWB pulses typically have durations on the order of nanoseconds, rise times of picoseconds and amplitudes around 100 kV m(-1). This article reviews current research on biological effects from HP/UWB exposure. The different references were classified according to endpoints (cardiovascular system, central nervous system, behavior, genotoxicity, teratology …). The article also reviews the aspects of mechanisms of interactions and tissue damage as well as the numerical work that has been done for studying HP/UWB pulse propagation and pulse energy deposition inside biological tissues. The mechanisms proposed are the molecular conformation change, the modification of chemical reaction rates, membrane excitation and breakdown and direct electrical forces on cells or cell constituents, and the energy deposition. As regards the penetration of biological matter and the deposited energy, mainly computations were published. They have shown that the EM field inside the biological matter is strongly modified compared to the incident EM field and that the energy absorption for HP/UWB pulses occurs in the same way as for continuous waves. However, the energy carried by a HP/UWB pulse is very low and the deposited energy is low. The number of published studies dealing with the biological effects is small and only a few pointed out slight effects. It should be further noted that the animal populations used in the studies were not always large, the statistical analyses not always relevant and the teams involved in this research rather limited in number.

Kinesin molecular motors serve a variety of cellular functions usually in dynamic processes. One characteristic feature of many kinesins is their ATP-dependent processive movement along polymerized microtubules. However, many kinesins work as stationary polymerases or depolymerases. Therefore, it needs to be determined for each motor, whether it moves processively along microtubules or not. The Schizosaccharomyces pombe kinesin-7, Tea2, has been shown to be involved in cell end marker transportation towards the cortex to organize the actin cytoskeleton. In human, kinesin 7 promotes microtubule polymerization. In Aspergillus nidulans, the machinery for determining growth directionality is conserved, but there is no evidence yet that kinesin 7, KipA is potentially involved in the transportation of the cell end marker proteins, TeaA or TeaR or newly identified proteins such as KatA. We expressed KipA in Escherichia coli and determined the catalytic properties of this kinesin. Here we show that KipA is an active ATPase, which is able to dimerize and move processively along microtubules with a speed of 9.48 μm/min.

Benzodiazepine effects on cholecystokinin tetrapeptide (CCK-4)-induced panic attack (PA) in humans are incompletely characterized, in particular on the neurofunctional level. This work explores the effects of lorazepam on brain activity and behavioral and physiological symptoms related to CCK-4-induced PA in healthy volunteers. Twenty-one male volunteers received 1 mg of lorazepam or placebo orally, 2 hours before an injection of 0.9% saline solution followed by 50 µg of CCK-4 during functional magnetic resonance imaging (fMRI) and heart rate recording. Panic attacks were defined using the panic symptom scale (PSS). In addition, the Y1-STAI (state anxiety) and the Bond & Lader Visual Analogue Scale (VAS) were used. Eleven subjects were classified as panickers. CCK-4 induced behavioral anxiety and cardiovascular effects along with cerebral activation in anxiety-related brain regions. Overall, lorazepam did not significantly modify the anxiogenic and cardiovascular effects of CCK-4. Regarding CCK-4-induced brain activation, lorazepam did not reduce activity in the insulae and cingulate gyrus of panickers. One milligram of lorazepam was not sufficient to reverse strong panicogenic effects, but decreased brain activity in the case of mild anxiety.

Objective: The effects of aging on the inhibitory function are largely described in the neuroimaging literature but little data is available on the beginning of this age-related impairment., Methods: In this study, we described the cortical activation of middle-aged (mean age +/- standard error to the mean, 51.7 +/- 3.1) subjects compared to young (26.8 +/- 3.4) and elderly subjects (62.8 +/- 3) while they performed a color-matched Stroop task during functional magnetic resonance imaging. The task consisted in identifying the printing color of a word regardless of its meaning. Three conditions were defined depending on the meaning of this word; neutral (no meaning), congruent (color name matching the printing color), incongruent (color name mismatching the printing color), with interference effect in the latter., Results: Middle-aged subjects were as slow as elderly compared to young for all conditions and both were less accurate than young subjects during interference condition. Elderly showed an activity more bilateral and greater in the parietal lobule, the dorsolateral and ventrolateral prefrontal cortex (DLPFC, VLPFC) during both congruent and incongruent conditions compared to young. Middle-aged showed an intermediary level of activity between those of elderly and young subjects in the left DLPFC, VLPFC and parietal lobule only during incongruent condition., Conclusion: These results suggested that the age-related impairment of the inhibitory process could already occur around the age of 50 years and consist in an increase of the activity in the left prefrontal and parietal cortex before increasing more and becoming bilateral around the age of 60 years., (Copyright (c) 2009 John Wiley & Sons, Ltd.)

A gfp reporter gene strain of Penicillium nordicum was constructed in order to be able to study the influence of environmental parameters on ochratoxin A biosynthesis. To introduce the gfp gene an Agrobacterium tumefaciens mediated transformation system (ATMT) for P. nordicum was established resulting in a transformation efficiency of about 60 transformants per microg of DNA. The selection principle was based on the hygromycin B resistance gene located on the TI-DNA fragment of the binary vector system. PCR and Southern blot hybridization revealed that the TI-DNA was integrated into the chromosome of P. nordicum. To show that the GFP protein can be used as a reporter gene in P. nordicum, this species was subsequently transformed with a vector, carrying a gfp gene under the control of the strong constitutive gpd promoter of A. nidulans. Moreover in this vector construction the gfp gene contained a stuA nuclear localization domain. Successful transformed strains showed a strong GFP activity located in the nuclei after light stimulation in contrast to the wild type which showed only very weak unspecific auto fluorescence under these conditions. Based on this proof of principle a vector was constructed in which the promoter of the otapksPN gene, the gene of the ochratoxin A polyketide synthase of P. nordicum was placed in front of the gfp gene. This construct was transformed into P. nordicum by ATMT and the resulting transformants were analysed by fluorescence microscopy. In these transformants the whole mycelial cells showed GFP activity after light stimulation, whereas the wild type strain did not. When the transformed strains were grown on medium which suppressed ochratoxin A biosynthesis, a very low level of fluorescence could be detected, whereas a high level of fluorescence was seen after growth on medium supportive for ochratoxin A biosynthesis.

Purpose: To evaluate the reproducibility of neural activations induced by an anticipatory anxiety provocation challenge in healthy volunteers., Materials and Methods: Fourteen healthy male volunteers participated in two separate functional MRI (fMRI) sessions in which they underwent a paradigm based on anticipation of aversive transcutaneous electrical nerve stimulations. This paradigm consisted of alternating presentation of red circles associated with the likelihood that aversive stimuli may be given and blue circles during which the subjects knew that no shock could be given. Anxiety state was compared before the fMRI sessions and during the threat periods using clinical scales (Hamilton, STAI-Y1), the Bond and Lader Visual Analogue Scale, and self-rating scales of apprehension and stimulus aversivity., Results: The selected paradigm induced anticipatory anxiety of moderate intensity as suggested by clinical scales and apprehension rating, without any habituation to the somatosensory stimulus across sessions. Compared to rest periods, threat of the aversive stimulus induced clear brain activation in anticipatory anxiety-related areas: frontal/prefrontal cortex, insula, lentiform nucleus, temporal pole, and cingulate cortex. Anxiety symptoms and cerebral activity were reproducible across sessions., Conclusion: The fMRI paradigm and its assessment method include all criteria to speed up the evaluation and the development of new anxiolytics.

The main objective of this work was to study the functional markers of the clinical response to cholecystokinin tetrapeptide (CCK-4). Twelve healthy male subjects were challenged with CCK-4 and simultaneously underwent functional magnetic resonance imaging (fMRI) recording. Since anticipatory anxiety (AA) is an intrinsic part of panic disorder, a behavioral paradigm, using the threat of being administered a second injection of CCK-4, has been developed to investigate induced AA. The study was composed of three fMRI scans according to an open design. During first and second scan, subjects were injected with placebo and CCK-4, respectively. The third scan was the AA challenge. CCK-4 administration induced physiological and psychological symptoms of anxiety that met the criteria for a panic attack in 8 subjects, as well as cerebral activation in anxiety-related brain regions. Clinical and physiological response intensity was consistent with cerebral activity extent and robustness. fMRI proved more sensitive than clinical assessment in evidencing the effects of the AA challenge. The latter induced brain activation, different from that obtained on CCK-4 and during placebo injection, that was likely related to anxiety. The method applied in this study is suitable for the study of anxiety using fMRI.

Despite the growing means devoted to research and development (R α D) and refinements in the preclinical stages, the efficiency of central nervous system (CMS) drug development is disappointing. Many drugs reach patient studies with an erroneous therapeutic indication andlor in incorrect doses. Apart from the first clinical studies, which are conducted in healthy volunteers and focus only on safety, iolerability, and pharmacokinetics, drug development mostly relies on patient studies. Psychiatric disorders are characterized by heterogeneity and a high rate of comorbidity. It is becoming increasingly difficult to recruit patients for clinical trials and there are many confounding factors in this population, for example, those related to treatments. In order to keep patient exposure and financial expenditure to a minimum, it is important to avoid ill-designed and inconclusive studies. This risk could be minimized by gathering pharmacodynamic data earlier in development and considering that the goal of a phase 1 plan is to reach patient studies with clear ideas about the compound's pharmacodynamic profile, its efficacy in the putative indication (proof of concept), and pharmacokinetic/pharmacodynamic relationships, in addition to safety, tolerability, and pharmacokinetics. Human models in healthy volunteers may be useful tools for this purpose, but their use necessitates a global adaptation of the phase scheme, favoring pharmacodynamic assessments without neglecting safety. We are engaged in an R α D program aimed to adapt existing models and develop new paradigms suitable for early proof of concept substantiation.

This report presents a non invasive method for studying oxygen consumption during photodynamic therapy in cultured cells. The oxygen partial pressure of perfusion medium flowing through cells cultured on microcarrier beads, was investigated before, during and after treatment. Pheophorbide a was used as a sensitiser. Time-dependent measurements demonstrate photochemical oxygen depletion induced by photosensitized reactions, followed by an oxygen pressure increase were attributed to a reduction in the cells' metabolism.

The metabolic response of Chinese Hamster Ovary (CHO) cells during photodynamic therapy (PDT) with hematoporphyrin IX (Hp IX) and pheophorbide (Ph) was monitored in real time by 31-phosphorous (31P) nuclear magnetic resonance (NMR) spectroscopy. The effects of the delivered light dose and of cell oxygenation were investigated. A delayed disappearance of nucleoside triphosphate (NTP) following irradiation was observed, which was related to the treatment efficiency. For cells irradiated with a light dose of 0.8 J/cm2 in the presence of Hp IX, the disappearance of the NTP peaks occurred within 30 minutes of irradiation, but for an irradiation of 0.24 J/cm2, the disappearance of the NTP peaks occurred about 6 hours later, and this delayed disappearance is related to the surviving fraction. For irradiation experiments involving Ph and a light dose of 0.036 J/cm2, NTP in injured cells began to decrease about 3 hours after irradiation, whereas for a light dose of 0.24 J/cm2, we observed the instantaneous disappearance of the NTP peaks occurring during the irradiation time. The same efficiency was obtained with two different oxygen partial pressures in the perfusate (360 and 154 mmHg) and a light dose of 0.24 J/cm2.

DNA cytometric measurements were performed with a TV image analysis system on 90 routine cytologic cervical smears from 18 women after automatic restaining of the smears with the Feulgen method. In the cytologic follow-up all the patients revealed borderline lesions (mild to moderate dysplasia) of the epithelium with koilocytosis. Since DNA aneuploidy is widely accepted as a marker for malignancy, an attempt was made to obtain a DNA diagnosis of prospective malignancy in these cases on the basis of the detection of single aneuploid cells. Because koilocytosis strongly suggests human papillomavirus infection, euploid polyploidy might result in up to 8c (c = haploid amount of DNA). Therefore, the aneuploidy detection threshold was set to 9c, excluding values around 16c and 32c (+/- 12.5%) to avoid false-positive diagnoses in cases of higher polyploidy values. The DNA diagnosis of malignancy was made in 13 patients. In 12 of them, carcinoma in situ was diagnosed in the histologic follow-up, resulting in 100% sensitivity of the DNA diagnosis. In five patients no cells greater than 9c were measured, leading to a benign DNA diagnosis. In the histologic follow-up, six patients revealed normal epithelium or moderate dysplasia. Thus, the specificity of the DNA diagnosis was 83.3%.