Expected resolution limits of x-ray free-electron laser single-particle imaging for realistic source and detector properties.

The unprecedented intensity of x-ray free-electron laser sources has enabled single-particle x-ray diffraction imaging (SPI) of various biological specimens in both two-dimensional projection and three dimensions (3D). The potential of studying protein dynamics in their native conditions, without crystallization or chemical staining, has encouraged researchers to aim for increasingly higher resolutions with this technique. The currently achievable resolution of SPI is limited to the sub-10 nanometer range, mainly due to background effects, such as instrumental noise and parasitic scattering from the carrier gas used for sample delivery. Recent theoretical studies have quantified the effects of x-ray pulse parameters, as well as the required number of diffraction patterns to achieve a certain resolution, in a 3D reconstruction, although the effects of detector noise and the random particle orientation in each diffraction snapshot were not taken into account. In this work, we show these shortcomings and address limitations on achievable image resolution imposed by the adaptive gain integrating pixel detector noise.

Complete response of advanced cutaneous squamous cell and basal cell carcinomas with sequential cemiplimab and sonidegib therapy.

A 78-year-old woman was referred to our skin cancer centre with three previous incomplete resections in the left cavum conchae of a deep-infiltrating locally advanced, but still asymptomatic basal cell carcinoma (BCC). The patient noted furthermore two rapidly growing exophytic lesions in the left preauricular and cervical area in the last weeks. The clinical and histological distinction of locally advanced from metastatic cutaneous squamous cell carcinoma (CSCC) lesions was challenging. Imaging analysis with CT scans showed, however, an involvement of the parotid gland as well as multiple small lymph node metastases. The interdisciplinary tumour board decision at our institution recommended a systemic treatment with the PD1-antibody cemiplimab. After 13 cycles with cemiplimab at a dose of 350 mg intravenously every 3-weeks, the patient showed a complete response of the two CSCC lesions with histological confirmation. However, the BCC of the left ear appeared to be unchanged and still asymptomatic. The interdisciplinary tumour board considered this tumour to be no candidate for a curative resection or irradiation. Therefore, the patient was exposed to the hedgehog inhibitor sonidegib with a conventional dose of 200 mg orally per day. After 3 months of treatment, the tumour showed a markable regression and a complete response was confirmed by 3-punch biopsies from this preoperated lesion. Both cemiplimab and sonidegib were excellently tolerated with almost no adverse events apart from a mild fatigue (CTC grade 1) over the first 3 weeks of the cemiplimab therapy. There were no laboratory abnormalities found.

Electrostatic fluctuations in collisional plasmas.

We present a theory of electrostatic fluctuations in two-component plasmas where electrons and ions are described by Maxwellian distribution functions at unequal temperatures. Based on the exact solution of the Landau kinetic equation, that includes electron-electron, electron-ion, and ion-ion collision integrals, the dynamic form factor, S(k[over ⃗],ω), is derived for weakly coupled plasmas. The collective plasma responses at ion-acoustic, Langmuir, and entropy mode resonances are described for arbitrary wave numbers and frequencies in the entire range of plasma collisionality. The collisionless limit of S(k[over ⃗],ω) and the strong-collision result based on the fluctuation-dissipation theorem and classical transport at T_{e}=T_{i} are recovered and discussed. Results of several Thomson scattering experiments in the broad range of plasma parameters are described and discussed by means of our theory for S(k[over ⃗],ω).

Comparative study of ligand binding during the postsynthetic stabilization of metal oxide nanoparticles.

In the absence of stabilizers in the reaction medium, the nonaqueous synthesis of metal oxide nanoparticles usually results in agglomerated products. Stabilization is however often possible in a postsynthetic treatment, involving the addition of organic ligands that coordinate to the nanoparticle surface. The ligands are commonly expected to chemisorb via functional groups; however, we have recently shown that also weakly and unspecifically interacting ligands can lead to stabilization. Here, we present detailed investigations on the stabilization, comparing the binding of weakly coordinating ligands to a system with strongly and selectively binding stabilizers and additionally exploring the effect of ligand chain length. Although in all cases stabilization and disintegration of agglomerates to the primary particle level are achieved, strong differences are observed with respect to the processes at the particle surface. Moreover, these processes are shown to be more complex than simple ligand adsorption and need to be understood for proper design and choice of stabilizers.

Insulin receptor substrate 2 expression and involvement in neuronal insulin resistance in diabetic neuropathy.

Insulin signaling depends on tyrosine phosphorylation of insulin receptor substrates (IRSs) to mediate downstream effects; however, elevated serine phosphorylation of IRS impairs insulin signaling. Here, we investigated IRS protein expression patterns in dorsal root ganglia (DRG) of mice and whether their signaling was affected by diabetes. Both IRS1 and IRS2 are expressed in DRG; however, IRS2 appears to be the prevalent isoform and is expressed by many DRG neuronal subtypes. Phosphorylation of Ser(731)IRS2 was significantly elevated in DRG neurons from type 1 and type 2 diabetic mice. Additionally, Akt activation and neurite outgrowth in response to insulin were significantly decreased in DRG cultures from diabetic ob/ob mice. These results suggest that DRG neurons express IRS proteins that are altered by diabetes similar to other peripheral tissues, and insulin signaling downstream of the insulin receptor may be impaired in sensory neurons and contribute to the pathogenesis of diabetic neuropathy.

In situ investigation of molecular kinetics and particle formation of water-dispersible titania nanocrystals.

Metal oxide nanoparticles can be fabricated under high control via nonaqueous sol-gel synthesis. This route has been shown to lead to highly crystalline, uniform nanostructures, which explains the high and growing interest it is receiving. The underlying mechanisms are, however, so far only rudimentarily understood on a molecular scale. Here, we applied in situ FTIR spectroscopy and other techniques to monitor the nonaqueous synthesis of titania nanoparticles that can be easily stabilised in polar solvents and thus, possess high potential for application. A special focus is put on the kinetics of the organic condensation mechanisms enabling the reaction of the precursor to the inorganic nanoparticles. By comparing these kinetics to the process of nanoparticle formation monitored via complementary methods such as TEM and dynamic light scattering, a detailed insight into the principles and mechanisms of nanoparticle formation via the nonaqueous sol-gel synthesis is achieved.

[Randomised clinical trial of an intensive intervention into life-styles of patients with hyperfibrinogenaemia in primary prevention of cardiovascular pathology in primary health care]. / Ensayo clínico aleatorizado de una intervención intensiva sobre los estilos de vida de pacientes con hiperfibrinogenemia en prevención primaria de las enfermedades cardiovasculares en el ámbito de la atención primaria de salud.

OBJECTIVES: To study the effect of an intensive programme to modify life-style on levels of plasma fibrinogen in patients without cardiovascular pathology, with high fibrinogen and normal cholesterol levels. To analyse whether the effect on fibrinogen is independent, or otherwise, of the effect on lipids. DESIGN: Randomised clinical trial with a control. SETTING: 11 health districts in L'Hospitalet de Llobregat and Barcelona. PARTICIPANTS: 436 patients will be included, 218 individuals between 35 and 75 years old in each group, and without cardiovascular pathology (ischaemic cardiopathy, cerebral vascular accident or peripheral arteriopathy), with hyperfibrinogenaemia (fibrinogen > 300 mg/dL) and with plasma control < 250 mg/dL. INTERVENTIONS: One group of patients will receive an intensive intervention (in frequency and intensity of counselling and treatment) for life-style changes, i.e. stopping smoking, low-calorie diet in case of overweight or obesity, and physical exercise. The follow-up of the intervention group will be every 2 months. The control group will follow customary treatments. MEASUREMENTS: Levels of plasma fibrinogen. In addition, other relevant events will be recorded over a 2-year monitoring period: modification of risk factors, changes in quality of life, cardiovascular events or death. DISCUSSION: The introduction of an intensive primary prevention intervention (life-style changes) in patients with hyperfibrinogenaemia could be a more effective measure than the habitual intervention for reducing plasma fibrinogen figures. In addition, these measures could be translated into a reduction of cardiovascular risk and an improvement in the patient s quality of life.

Ensayo clínico aleatorizado de una intervención intensiva sobre los estilos de vida de pacientes con hiperfibrinogenemia en prevención primaria de las enfermedades cardiovasculares en el ámbito de la atención primaria de salud / Randomised clinical trial of an intensive intervention into life-styles of patients with hyperfibrinogenaemia in primary prevention of cardiovascular pathology in primary health care

Objetivos. Estudiar el efecto de un programa intensivo de modificación del estilo de vida en los valores de fibrinógeno plasmático en pacientes sin enfermedad cardiovascular, con fibrinógeno elevado y valores normales de colesterol. Analizar si el efecto sobre el fibrinógeno es independiente del efecto sobre los lípidos. Diseño. Ensayo clínico controlado y aleatorizado. Emplazamiento. Once áreas básicas de L’Hospitalet de Llobregat y Barcelona. Participantes . Se incluirá a 436 pacientes,218 en cada grupo, de 35-75 años, sin enfermedad cardiovascular (cardiopatía isquémica, accidente cerebrovascular y arteriopatía periférica) con hiperfibrinogenemia (fibrinógeno > 300mg/dl) y colesterol plasmático < 250 mg/dl. Intervenciones. Un grupo de pacientes recibirá una intervención intensiva (en frecuencia e intensidad del consejo y tratamiento) sobre cambios de estilo de vida: dejar de fumar, dieta hipocalórica encaso de sobrepeso u obesidad y ejercicio físico. El seguimento del grupo intervención se realizará cada 2 meses. El grupo control seguirá los cuidados habituales. Mediciones. Se determinarán los valores de fibrinógeno plasmático. Además, se registrarán otros acontecimientos de interés(modificación de los factores de riesgo, cambios en la calidad de vida, acontecimientos cardiovasculares y muerte)durante un seguimiento de 2 años. Discusión. La instauración de una intervención intensiva de prevención primaria (cambios de estilo de vida) en los pacientes que presentan hiperfibrinogenemia podría ser una medida más eficaz que la intervención habitual para reducir las cifras de fibrinógeno plasmático. Además, estas medidas podrían traducirse en una disminución del riesgo cardiovascular y en una mejora de la calidad de vida del paciente

Objectives. To study the effect of an intensive programme to modify life-style on levels of plasma fibrinogen in patients without cardiovascular pathology, with high fibrinogen and normal cholesterol levels. To analyse whether the effect on fibrinogen is independent, or otherwise, of the effect on lipids. Design. Randomised clinical trial with a control. Setting. 11 health districts in L’Hospitalet deLlobregat and Barcelona. Participants. 436 patients will be included, 218individuals between 35 and 75 years old in each group, and without cardiovascular pathology(ischaemic cardiopathy, cerebral vascular accident or peripheral arteriopathy), with hyperfibrinogenaemia(fibrinogen › 300 mg/dL) and with plasma control‹250 mg/dL. Interventions. One group of patients will receive an intensive intervention (in frequency and intensity of counselling and treatment) for life-style changes, i.e. stopping smoking, low-calorie diet incase of overweight or obesity, and physical exercise. The follow-up of the intervention group will be every 2 months. The control group will follow customary treatments. Measurements. Levels of plasma fibrinogen. In addition, other relevant events will be recorded over a 2-year monitoring period: modification of risk factors, changes in quality of life, cardiovascular events or death. Discussion. The introduction of an intensive primary prevention intervention (life-style changes) in patients with hyperfibrinogenaemia could be a more effective measure than the habitual intervention for reducing plasma fibrinogen figures. In addition, these measures could be translated into a reduction of cardiovascular risk and an improvement in the patient´s quality of life

[Relationship between cholesterol and fibrinogen in two populations of different geographical location of Catalonia]. / Relación entre colesterol y fibrinógeno en dos poblaciones de distinta localización geográfica de Cataluña.

OBJECTIVES: Verification of the following in two different geographical location populations (seashore and mountain) with cardiovascular symptomatology: 1) the prevalence of hyperfibrinogenemia and possible correlation with cholesterolemia; 2) the differences between both populations in the profiles of these parameters. DESIGN: Cross-sectional descriptive study. CONTEXT: Primary Care. PARTICIPANTS: Three hundred and seventy five patients who went to two hospitals between May 1995 and July 1998. In the seashore center 256 patients and in the mountain center 119 patients. MAIN MEASUREMENTS: Clinical history and analytical parameters. Fibrinogen (FBG), indirect prothrombin time, enzymatic cholesterol (CLT) Utachi 717. The patients were sorted out into 4 groups: 1) high FBG > 300 mg/dl and high CLT > 240 mg/dl; 2) high FBG > 300 and low CLT < 240; 3) low FBG < 300 and high CLT > 240, and 4) low FBG < 300 and low CLT < 240. RESULTS: Levels of FBG: homogeneous between groups 1 and 2 (high) and 3 and 4 (low), and different between upper and lower groups. Cholesterol showed the same behavior. Group 1 with a similar number of patients in mountain and seashore (40% and 41%). Group 2 with 42.8% of patients from mountain and 26.9% from seashore. Groups 3 and 4 are presented with lower percentages. We did not find correlation between the levels of FBG and those of CLT. CONCLUSIONS: Predominance of patients with high FBG and normal CLT (group 2) in the mountain cohort, in contrast with a higher prevalence of normal FBG and high CLT (group 3) in the seashore cohort. In participants with normal levels or with high risk the variations of the FBG were not dependent nor related to those of CLT.

Effect of lazaroid pretreatment on dopamine-induced impairment of the rat nigrostriatal system.

Oxidative stress induced by enhanced catecholamine metabolism may subsequently cause damages to the nervous system. We used in vivo-pulse voltammetry to study an enhanced brain dopamine (metabolism) induced either by intranigral dopamine (DA) injection or reduction of cerebral blood flow. One week after intranigral injection of 10 microg DA or unilateral occlusion of one carotid the DA activity in the ipsilateral striatum was decreased as compared to the contralateral side. Three weeks after DA application and carotid clamping the DA activity was restored to normal. The significant reduction of 3,4-dihydroxyphenylacetic acid (DOPAC) after one week was attenuated by pretreatment with the lazaroid U-74389G, injected 20 min before surgery. The results are in accordance with the view that radical mechanisms play a crucial role in the impairment of the nigrostriatal system induced by oligemia.

Excitatory stimulation of neurons in the arcuate nucleus inhibits gastric acid secretion via vagal pathways in anesthetized rats.

It is well established that autonomic control of gastrointestinal function is modulated by central autonomic neurotransmission. In this context it has been shown that gastrointestinal motility and secretion can be modulated by exogenous neuropeptides microinjected into the paraventricular nucleus of the hypothalamus (PVN). Furthermore, there is considerable evidence suggesting that neurons projecting from the arcuate nucleus (Arc) to the PVN may be the source of endogenous neuropeptide release in the PVN. This poses the question whether stimulation of neurons in the arcuate nucleus, e.g. by an excitatory amino acid, alters gastrointestinal function. In the present study, we investigated the effect of an excitatory amino acid, kainate, microinjected into the arcuate nucleus on gastric acid secretion in urethane-anesthetized rats. Kainate (140 pmol/rat) bilaterally microinjected into the Arc induced an significant inhibition of pentagastrin (PG) stimulated (16 mg/kg per h) gastric acid secretion throughout an observation period of 120 min after microinjection. Microinjection of kainate into hypothalamic areas outside the arcuate nucleus did not modify gastric secretion. Bilateral cervical vagotomy blocked the effect of kainate injected into the Arc on PG-stimulated gastric acid secretion. These data show that gastric secretory function can be modulated by stimulation of neuronal activity in the Arc via efferent vagal pathways. The results suggest that the arcuate nucleus is a forebrain area involved in the CNS regulation of gastrointestinal function.

Involvement of CCK in the paraventricular nucleus of the hypothalamus in the CNS regulation of colonic motility.

The effects of cholecystokinin octapeptide (CCK(8)), the CCK-A receptor antagonist, MK-329, and the CCK-B receptor antagonist, L-365, 260, microinfused into the paraventricular nucleus of hypothalamus (PVN) on colonic motor function was investigated in awake rats, chronically implanted with a microinjection cannula into the PVN and a catheter into the proximal colon. In fasted rats, bilateral microinfusion of CCK(8) at doses of 1.5 and 3.0 microg/rat into the PVN stimulated colonic transit, as shown by a significant increase in the geometric center by 47 and 54%, respectively. This effect of CCK(8) was site-specific to the PVN, since microinjection of the peptide into sites outside of but adjacent to PVN had no effect. In non-fasted rats, L-365,260 bilaterally microinjected into the PVN at a dose of 1.5 microg/rat inhibited propulsive colonic motor function; colonic transit time significantly increased by 73% in comparison to the control condition. Microinfusion of the CCK-A antagonist into in the PVN did not affect colonic transit. These results show that the PVN is a responsive site for the central CCK(8)-induced modulation of colonic motility. The data suggest, that endogenous CCK in the paraventricular nucleus of the hypothalamus unfolds a stimulatory effect on colonic transit through action on CCK-B receptors.

Neuropeptide Y in the paraventricular nucleus of the hypothalamus stimulates colonic transit by peripheral cholinergic and central CRF pathways.

There is evidence suggesting that neuropeptide Y (NPY) as well as corticotropin-releasing factor (CRF) in the paraventricular nucleus of the hypothalamus (PVN) are involved in the CNS regulation of gastrointestinal (GI) function. We studied the effects of NPY or Y1-and Y2-receptor agonists microinjected into the PVN on colonic transit. Microinjection of NPY into the PVN at doses of 0.15-1.5 microg decreased the colonic transit time of conscious rats up to 49%. Pretreatment with the peripherally acting cholinergic antagonist atropine methyl nitrate (0.1 mg kg-1 i.p.) blocked the NPY into PVN-induced effect on colonic motor function.The agonist of the Y1-receptor, NPY(Leu31, Pro34), as well as the Y2-receptor agonist, NPY(13-36), dose-dependently decreased colonic transit time when microinjected into the PVN (0.05, 0.15 and 0.5 microg). However, the Y1-receptor agonist was more effective. Intracerebroventricular (ICV) application of the CRF-receptor antagonist, alpha-helical-CRF9-41 (50 microg/rat), blocked the NPY effect in the PVN on colonic motor function. In conclusion, stimulation of colonic transit by NPY acting in the PVN was observed. The PVN is more sensitive to agonists acting on the Y1- than on the Y2-receptor to mediate stimulation of propulsive colonic motility. The effect of NPY in the PVN on colonic motor function depends on central CRF and peripheral cholinergic pathways.

Bromal-derived tetrahydro-beta-carbolines as neurotoxic agents: chemistry, impairment of the dopamine metabolism, and inhibitory effects on mitochondrial respiration.

The mammalian alkaloids tryptoline (1) and eleagnine (2) as well as the highly halogenated (X = F, Cl, Br) tetrahydro-beta-carbolines (THbetaCs) 3-5, structurally similar to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 6), were found to have a common feature of inducing a severe impairment of the nigrostriatal dopamine metabolism and inhibiting complex I of the mitochondrial respiratory chain highly selectively. Within the series of compounds tested, 1-tribromomethyl-1,2,3,4-tetrahydro-beta-carboline ('TaBro', 5), which was prepared in high yields from the biogenic amine tryptamine ('Ta', 7) and the unnatural aldehyde bromal ('Bro', 8) by a Pictet-Spengler cyclization reaction, turned out to be the most potent toxin in vitro and in vivo. As demonstrated by voltammetric measurements on rats, for all the THbetaCs 1-5 investigated, intranigral application of a single dose of 10 microg resulted in a significant reduction of the dopaminergic activity in the striatum, with the strongest effect being observed for TaBro (5). Using rat brain homogenates, again 5 (IC50 = 200 microM) as well as its dehydrohalogenation product 11 (IC50 = 150 microM) exhibited the most pronounced inhibitory potential on mitochondrial respiration. The halogen-free THbetaCs 1 and 2 as well as the MPTP metabolite 1-methyl-4-phenylpyridinium ion (MPP+), by contrast, showed only a moderate inhibition at concentrations in the millimolar range (e.g. for MPP+: IC50 = 3.5 mM). For an elucidation of the role of hydrophobic portion in the inhibitory action against complex I activity, several N-acyl derivatives (15-21) of 5 were synthesized and tested. An X-ray diffraction study on the 3-dimensional structure of trifluoroacetylated highly halogenated THbetaCs (12-14) revealed the tetrahydropyrido part to adopt a nearly planarized half-chair conformation. Because of the steric demand of the trihalogenmethyl moiety (CF3 < CCl3 < CBr3), the N-substituent is dramatically pushed out of that ring 'plane'.

Responses to perceived unethical practices in clinical neuropsychology: ethical and legal considerations.

Neuropsychologists often review the work of colleagues who have performed a neuropsychological evaluation. At times, these reviews may cause one to believe that a colleague acted in an unethical manner. However, it is often unclear whether the situation warrants contacting the colleague or filing a complaint. This article provides examples of potential unethical practices in neuropsychology, and then reviews the relevant ethical principles and legal precedents concerning the obligations and possible risks of reporting perceived unethical practices of a colleague. The paper concludes with a series of recommendations and options as to when and how one should proceed in such situations.

Performance of compensation seeking and non-compensation seeking samples on the Victoria symptom validity test: cross-validation and extension of a standardization study.

Previous research suggests that the Victoria Symptom Validity Test (VSVT) is effective in confirming or disconfirming the validity of a patient's reported cognitive impairments. We sought to cross-validate the findings of the VSVT standardization study, and to determine cut-off scores that are most efficient in discriminating our samples of compensation-seeking patients, primarily with mild traumatic brain injury (CS; n = 53), and non-compensation seeking patients with intractable seizures (NCS; n = 30). All patients in the NCS sample scored in the "valid" range on the VSVT difficult memory items, compared to only 58.5% of the CS sample. We also identified VSVT measures and cut-off scores maximally efficient in discriminating these samples. This study confirms previous research that non-compensation seeking patients do well on the VSVT, but that many compensation seeking patients perform poorly on this measure.