A non-coding RNA balancing act: miR-346-induced DNA damage is limited by the long non-coding RNA NORAD in prostate cancer.

BACKGROUND: miR-346 was identified as an activator of Androgen Receptor (AR) signalling that associates with DNA damage response (DDR)-linked transcripts in prostate cancer (PC). We sought to delineate the impact of miR-346 on DNA damage, and its potential as a therapeutic agent. METHODS: RNA-IP, RNA-seq, RNA-ISH, DNA fibre assays, in vivo xenograft studies and bioinformatics approaches were used alongside a novel method for amplification-free, single nucleotide-resolution genome-wide mapping of DNA breaks (INDUCE-seq). RESULTS: miR-346 induces rapid and extensive DNA damage in PC cells - the first report of microRNA-induced DNA damage. Mechanistically, this is achieved through transcriptional hyperactivation, R-loop formation and replication stress, leading to checkpoint activation and cell cycle arrest. miR-346 also interacts with genome-protective lncRNA NORAD to disrupt its interaction with PUM2, leading to PUM2 stabilisation and its increased turnover of DNA damage response (DDR) transcripts. Confirming clinical relevance, NORAD expression and activity strongly correlate with poor PC clinical outcomes and increased DDR in biopsy RNA-seq studies. In contrast, miR-346 is associated with improved PC survival. INDUCE-seq reveals that miR-346-induced DSBs occur preferentially at binding sites of the most highly-transcriptionally active transcription factors in PC cells, including c-Myc, FOXA1, HOXB13, NKX3.1, and importantly, AR, resulting in target transcript downregulation. Further, RNA-seq reveals widespread miR-346 and shNORAD dysregulation of DNA damage, replication and cell cycle processes. NORAD drives target-directed miR decay (TDMD) of miR-346 as a novel genome protection mechanism: NORAD silencing increases mature miR-346 levels by several thousand-fold, and WT but not TDMD-mutant NORAD rescues miR-346-induced DNA damage. Importantly, miR-346 sensitises PC cells to DNA-damaging drugs including PARP inhibitor and chemotherapy, and induces tumour regression as a monotherapy in vivo, indicating that targeting miR-346:NORAD balance is a valid therapeutic strategy. CONCLUSIONS: A balancing act between miR-346 and NORAD regulates DNA damage and repair in PC. miR-346 may be particularly effective as a therapeutic in the context of decreased NORAD observed in advanced PC, and in transcriptionally-hyperactive cancer cells.

Urine Extracellular Vesicle GATA2 mRNA Discriminates Biopsy Result in Men with Suspicion of Prostate Cancer.

PURPOSE: Prostate specific antigen has limited performance in detecting prostate cancer. The transcription factor GATA2 is expressed in aggressive prostate cancer. We analyzed the predictive value of urine extracellular vesicle GATA2 mRNA alone and in combination with a multigene panel to improve detection of prostate cancer and high risk disease. MATERIALS AND METHODS: GATA2 mRNA was analyzed in matched extracellular vesicles isolated from urines before and after prostatectomy (16) and paired urine and tissue prostatectomy samples (19). Extracellular vesicle GATA2 mRNA performance to distinguish prostate cancer and high grade disease was tested in training (52) and validation (165) cohorts. The predictive value of a multigene score including GATA2, PCA3 and TMPRSS2-ERG (GAPT-E) was tested in both cohorts. RESULTS: Confirming its prostate origin, urine extracellular vesicle GATA2 mRNA levels decreased significantly after prostatectomy and correlated with prostate cancer tissue GATA2 mRNA levels. In the training and validation cohort GATA2 discriminated prostate cancer (AUC 0.74 and 0.66) and high grade disease (AUC 0.78 and 0.65), respectively. Notably, the GAPT-E score improved discrimination of prostate cancer (AUC 0.84 and 0.72) and high grade cancer (AUC 0.85 and 0.71) in both cohorts when compared with each biomarker alone and PT-E (PCA3 and TMPRSS2-ERG). A GAPT-E score for high grade prostate cancer would avoid 92.1% of unnecessary prostate biopsies, compared to 61.9% when a PT-E score is used. CONCLUSIONS: Urine extracellular vesicle GATA2 mRNA analysis improves the detection of high risk prostate cancer and may reduce the number of unnecessary biopsies.

High concentration aqueous magnetic fluids: structure, colloidal stability, magnetic and flow properties.

This paper is an in-depth analysis devoted to two basic types of water based magnetic fluids (MFs), containing magnetite nanoparticles with electrostatic and with electro-steric stabilization, both obtained by chemical coprecipitation synthesis under atmospheric conditions. The two sets of magnetic fluid samples, one with citric acid (MF/CA) and the other with oleic acid (MF/OA) coated magnetic nanoparticles, respectively, achieved saturation magnetization values of 78.20 kA m-1 for the electrostatically and 48.73 kA m-1 for the electro-sterically stabilized aqueous ferrofluids which are among the highest reported to date. A comprehensive comparative analysis combining electron microscopy, X-ray photoelectron spectroscopy, attenuated total reflectance Fourier transform infrared spectroscopy, vibrating sample magnetometry, small-angle X-ray and neutron scattering, dynamic light scattering and magneto-rheometry revealed similarities and essential differences on the microscopic and macroscopic level between the two kinds of water-based ferrofluids. While the saturation magnetization values are quite different, the hydrodynamic volume fractions of the highest concentration MF/CA and MF/OA samples are practically the same, due to the significantly different thicknesses of the particles' coating layers. The results of volume fraction dependent structure analyses over a large concentration range by small-angle X-ray and neutron scattering, correlated with magneto-rheological investigations for the electrostatically stabilized MFs, demonstrate formation of short chains of magnetic nanoparticles which are relatively stable against coagulation with increasing concentration, while for MFs with electro-steric stabilization, magnetic field and shear rate dependent loosely bound structures are observed. These particle structures in MF/OA samples manifest themselves already at low volume fraction values, which can be attributed mainly to magnetic interactions of larger size particles, besides non-magnetic interactions mediated by excess surfactant.

Neurostimulation for Parkinson's disease with early motor complications.

BACKGROUND: Subthalamic stimulation reduces motor disability and improves quality of life in patients with advanced Parkinson's disease who have severe levodopa-induced motor complications. We hypothesized that neurostimulation would be beneficial at an earlier stage of Parkinson's disease. METHODS: In this 2-year trial, we randomly assigned 251 patients with Parkinson's disease and early motor complications (mean age, 52 years; mean duration of disease, 7.5 years) to undergo neurostimulation plus medical therapy or medical therapy alone. The primary end point was quality of life, as assessed with the use of the Parkinson's Disease Questionnaire (PDQ-39) summary index (with scores ranging from 0 to 100 and higher scores indicating worse function). Major secondary outcomes included parkinsonian motor disability, activities of daily living, levodopa-induced motor complications (as assessed with the use of the Unified Parkinson's Disease Rating Scale, parts III, II, and IV, respectively), and time with good mobility and no dyskinesia. RESULTS: For the primary outcome of quality of life, the mean score for the neurostimulation group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (between-group difference in mean change from baseline to 2 years, 8.0 points; P=0.002). Neurostimulation was superior to medical therapy with respect to motor disability (P<0.001), activities of daily living (P<0.001), levodopa-induced motor complications (P<0.001), and time with good mobility and no dyskinesia (P=0.01). Serious adverse events occurred in 54.8% of the patients in the neurostimulation group and in 44.1% of those in the medical-therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of the patients in the neurostimulation group and for 94.5% of those in the medical-therapy group. CONCLUSIONS: Subthalamic stimulation was superior to medical therapy in patients with Parkinson's disease and early motor complications. (Funded by the German Ministry of Research and others; EARLYSTIM ClinicalTrials.gov number, NCT00354133.).

Integrative molecular profiling of routine clinical prostate cancer specimens.

BACKGROUND: Comprehensive molecular profiling led to the recognition of multiple prostate cancer (PCa) molecular subtypes and driving alterations, but translating these findings to clinical practice is challenging. PATIENTS AND METHODS: We developed a formalin-fixed paraffin-embedded (FFPE) tissue compatible integrative assay for PCa molecular subtyping and interrogation of relevant genetic/transcriptomic alterations (MiPC). We applied MiPC, which combines capture-based next generation sequencing and quantitative reverse transcription PCR (qRT-PCR), to 53 FFPE PCa specimens representing cases not well represented in frozen tissue cohorts, including 8 paired primary tumor and lymph node metastases. Results were validated using multiplexed PCR based NGS and Sanger sequencing. RESULTS: We identified known and novel potential driving, somatic mutations and copy number alterations, including a novel BRAF T599_V600insHT mutation and CYP11B2 amplification in a patient treated with ketoconazole (a potent CYP11B2 inhibitor). qRT-PCR integration enabled comprehensive molecular subtyping and provided complementary information, such as androgen receptor (AR) target gene module assessment in advanced cases and SPINK1 over-expression. MiPC identified highly concordant profiles for all 8 tumor/lymph node metastasis pairs, consistent with limited heterogeneity amongst driving events. MiPC and exome sequencing were performed on separately isolated conventional acinar PCa and prostatic small cell carcinoma (SCC) components from the same FFPE resection specimen to enable direct comparison of histologically distinct components. While both components showed TMPRSS2:ERG fusions, the SCC component exclusively harbored complete TP53 inactivation (frameshift variant and copy loss) and two CREBBP mutations. CONCLUSIONS: Our results demonstrate the feasibility of integrative profiling of routine PCa specimens, which may have utility for understanding disease biology and enabling personalized medicine applications.

Olfactory function in Parkinson's Disease - effects of training.

BACKGROUND: Up to 90% of patients with Parkinson's disease (PD) exhibit olfactory dysfunction, but little is known about the effects of olfactory training. The study aim was to investigate whether the ability to identify olfactory stimuli can be improved by means of a brief training session. Furthermore, the impact of hyposmia on quality of life in PD was investigated by means of a questionnaire. METHODS: Olfactory function was rated in 34 patients with PD and in 26 controls before and after a training session. An additional 20 patients with PD served as a control group and were tested twice without an intervening training session. Long-term effects were evaluated in a small subset of patients. Cognitive tests and DaT SPECT scans were performed. RESULTS: We demonstrated significant same-day and long-term training effects in trained PD patients compared with non-trained PD patients. A slightly significant correlation was seen between the training effect and DaT putamen values, but not with cognitive test scores. Furthermore, patients with PD reported that hyposmia significantly decreased their quality of life. CONCLUSIONS: Patients with PD improved the number of correctly identified odors in an olfactory test through a brief training session. Olfactory training may have potential in rehabilitation of patients with PD.

The association of metabolic syndrome and psoriasis: a population- and hospital-based cross-sectional study.

BACKGROUND: Psoriasis (PS) has been suggested to be associated with the metabolic syndrome (MetS) in numerous studies with conflicting results. The vast majority of previous data were based on PS subjects from hospitals, and when based on data from the general population the PS subjects were often identified in insurance health databases. Furthermore, many studies used a single method approach, e.g. self-reported diagnosis. OBJECTIVE: We have therefore investigated a possible association between PS and MetS on PS subjects from the hospital as well as the general population using combined methods, i.e. self-reported diagnosis, physical examinations and blood samples. METHODS: A population- and hospital-based cross-sectional study of the possible association between PS and MetS. RESULTS: Thirty-six hospital PS subjects, 860 population PS subjects and 14,016 non-PS subjects were identified. The odds ratios (ORs) for hospital PS subjects and population PS subjects vs. population non-PS subjects, respectively, were 5.14 (2.47-10.69) and 1.29 (1.09-1.53) for MetS, 4.55 (1.91-10.85) and 1.16 (0.85-1.59) for diabetes, 1.92 (0.87-4.22) and 1.00 (0.86-1.17) for hypertension, 4.34 (1.86-10.10) and 1.15 (1.00-1.34) for hypertriglyceridaemia, 3.88 (1.96-7.69) and 1.19 (1.01-1.42) for hypoHDL, 5.77 (2.89-11.52) and 1.19 (1.00-1.41) for general obesity and 2.92 (1.45-5.88) and 1.34 (1.16-1.55) for abdominal obesity. Obesity acted as a possible confounder. A uniform pattern of higher ORs for hospital PS subjects when compared to population PS subjects was observed. The severity and duration of PS did not seem to affect the results. As this is a cross-sectional study we cannot demonstrate causality. CONCLUSION: The data suggested an association between PS and MetS as well as its individual parameters on a hospital-based level, with the exception of hypertension. On a population-based level the associations were only significant for MetS, hypoHDL and abdominal obesity.

Self-reported skin morbidities and health-related quality of life: a population-based nested case-control study.

BACKGROUND: Impaired dermatological health-related quality of life (HRQoL) has been observed in hospital-based studies, but little is known on a population-based level. OBJECTIVE: To investigate self-reported dermatological HRQoL in the general population. METHODS: Hidradenitis suppurativa, psoriasis, pimples, hand rash or atopic eczema were identified using questionnaires in a 15,177 person population sample. A nested case-control study of 180 cases and 259 controls was made using the Dermatology Life Quality Index (DLQI), Skindex-29 and EQ-5D. RESULTS: Cases had higher scores in DLQI and Skindex-29 and a lower score in EQ-5D, suggesting lower HRQoL. Adjusting for age and sex, the differences in Skindex-29 and DLQI were significant (p < 0.001). CONCLUSIONS: Persons with self-reported skin morbidity had lower HRQoL than the general population. The impairment is not as significant as in studies of hospital-based cases, but considering the high prevalence of skin diseases it may still represent a significant burden of disease on society in aggregate.

Combined DaT imaging and olfactory testing for differentiating parkinsonian disorders.

OBJECTIVE: Dopamine transporter (DaT) imaging with single photon emission computed tomography (SPECT) detects loss of striatal dopaminergic innervation with very high sensitivity. It cannot readily distinguish idiopathic Parkinson's disease (iPD) and dementia with Lewy bodies (DLB) from atypical disorders (aPD). However, most iPD/DLB patients are hyposmic, whereas the majority of aPD patients were reported to have intact olfaction. For this reason, we conducted a longitudinal follow-up study to investigate the power of combined DaT imaging and olfactory testing to predict the final diagnosis of the patients. MATERIALS AND METHODS: A total of 129 patients received [123I]FP-CIT SPECT and olfactory testing at baseline assessment. Clinical follow-up 30 ± 12 months later was the diagnostic standard of truth. A normative dataset of 24 healthy controls was used for comparison. RESULTS: Baseline DaT imaging predicted a dopamine-deficient diagnosis with 98% sensitivity and 98% specificity. The combined DaT/olfactory testing correctly classified 91% of patients as iPD/DLB (PPV 91%). The PPV rose to 97% or greater in anosmic patients. In contrast, only 45% of aPD patients were categorised correctly by combined DaT/olfactory testing - mainly because of the presence of normosmic iPD patients. CONCLUSIONS: In patients with an abnormal DaT SPECT, hyposmia yields an a posteriori likelihood of iPD/DLB of > 90%. In contrast, a finding of normosmia only increases the a posteriori likelihood of aPD to approximately the 50%.

Effects of an isocaloric healthy Nordic diet on insulin sensitivity, lipid profile and inflammation markers in metabolic syndrome -- a randomized study (SYSDIET).

BACKGROUND: Different healthy food patterns may modify cardiometabolic risk. We investigated the effects of an isocaloric healthy Nordic diet on insulin sensitivity, lipid profile, blood pressure and inflammatory markers in people with metabolic syndrome. METHODS: We conducted a randomized dietary study lasting for 18-24 weeks in individuals with features of metabolic syndrome (mean age 55 years, BMI 31.6 kg m(-2) , 67% women). Altogether 309 individuals were screened, 200 started the intervention after 4-week run-in period, and 96 (proportion of dropouts 7.9%) and 70 individuals (dropouts 27%) completed the study, in the Healthy diet and Control diet groups, respectively. Healthy diet included whole-grain products, berries, fruits and vegetables, rapeseed oil, three fish meals per week and low-fat dairy products. An average Nordic diet served as a Control diet. Compliance was monitored by repeated 4-day food diaries and fatty acid composition of serum phospholipids. RESULTS: Body weight remained stable, and no significant changes were observed in insulin sensitivity or blood pressure. Significant changes between the groups were found in non-HDL cholesterol (-0.18, mmol L(-1) 95% CI -0.35; -0.01, P = 0.04), LDL to HDL cholesterol (-0.15, -0.28; -0.00, P = 0.046) and apolipoprotein B to apolipoprotein A1 ratios (-0.04, -0.07; -0.00, P = 0.025) favouring the Healthy diet. IL-1 Ra increased during the Control diet (difference -84, -133; -37 ng L(-1) , P = 0.00053). Intakes of saturated fats (E%, beta estimate 4.28, 0.02; 8.53, P = 0.049) and magnesium (mg, -0.23, -0.41; -0.05, P = 0.012) were associated with IL-1 Ra. CONCLUSIONS: Healthy Nordic diet improved lipid profile and had a beneficial effect on low-grade inflammation.

The ileal and total tract digestibility fibre and nutrients in pigs fed high-fibre cereal-based diets provided without and with a carbohydrase complex.

The effect of carbohydrase can be variable according to the complexity of cereal grains and co-products. Studies on the effect of carbohydrase on cereal diets varying in complexity are scarce. This study was conducted to investigate the apparent ileal (AID) and total tract digestibility (ATTD) of energy, fibre and nutrients in pigs fed diets based on cereal grains and co-products without and with supplementation with a carbohydrase complex in the form of xylanase, arabinofuranosidase and ß-glucanase. The experiment was carried out as an 8 × 4 Youden Square design (eight diets and four periods by two blocks) using 16 growing pigs (33.3 ± 0.8 kg) surgically fitted with a T-cannula in the terminal ileum. The pigs were fed eight experimental diets based on either - maize, wheat, rye, or a wheat and rye mix that were provided with or without enzyme supplementation. The AID and ATTD of DM, organic matter, energy, CP, fat, starch, and soluble and insoluble non-starch polysaccharides (NSPs) were studied using titanium dioxide as an indigestible marker. There was a cereal type effect (P < 0.05) of the AID of most of the nutrients investigated but ash and NSP and some of its constituents but with no interactions between cereal types and carbohydrase supplementation (P > 0.05). The ATTD of nutrients in the large intestine was mainly influenced by the fibre composition and was significantly lower (P < 0.001) for NSP, protein and energy for the Maize than the other diets. Supplementation of the cereal diets with the carbohydrase complex partially degrades arabinoxylan (AX) and ß-glucan giving rise to a generally higher AID of high-molecular weight arabinoxylan (P = 0.044), starch (P = 0.042), a tendency (P < 0.10) of higher AID of non-cellulosic polysaccharide glucose residue (ß-glucan) and soluble arabinoxylan (AX) whereas none of the other components were affected (P > 0.05). Collectively, the results indicate that the carbohydrase complex degrades AX in the stomach and small intestine, leading to a higher AID but with no influence on the ATTD of fibres, nutrients, and energy.

Dipolar structuring of organically modified fluorohectorite clay particles.

This report focuses on both the characterization of organically modified fluorohectorite (Fh) clay particles and their electric-field-induced alignment when suspended in a non-polar liquid (silicone oil). Thermal decomposition temperatures of the surfactant molecules adsorbed on the clay surfaces and those being intercalated between clay crystalline layers were measured by thermal gravimetric analysis (TGA). Zeta potential measurements confirmed the successful modification of the clay surfaces. Optical microscopy observations showed that the sedimentation of modified particles was much slower compared to that of the non-modified system. It was shown that organic modification has a significant effect on colloidal stability of the system, preventing particles from forming large aggregates when suspended in a non-polar liquid. There are also signs of a slight increase in overall alignment of the clay particles when exposed to in an electric field, with the nematic order parameter (S(2)) being higher for the organically modified particles, compared to that of the non-modified counterparts. This behaviour is mainly a result of the formation of smaller and more uniform aggregates, in contrast to the large aggregate structures formed by non-modified clay particles.

Influence of dietary fibre on nutrient digestibility and energy utilisation in growing pigs fed diets varying in soluble and insoluble fibres from co-products.

The co-products from the industry are used to reduce costs in pig diets. However, the co-products used in pig diets are limited because of a high fibre content which is not digested by endogenous enzymes and is resistant to degradation in the small and large intestines. The aim of this study was to investigate digestibility of nutrients and energy, and energy utilisation in pigs fed diets with various soluble and insoluble dietary fibre (DF) from co-products. The experiment was performed as a 4 × 4 Latin square design (four diets and four periods) using four growing pigs (66.2 ±â€¯7.8 kg) surgically fitted with a T-cannula in the end of the small intestine. The pigs were fed four experimental diets: low-fibre control (LF), high-fibre control (HF), high-soluble fibre (HFS) and high-insoluble fibre (HFI) diets. The apparent ileal digestibility (AID) and apparent total tract digestibility (ATTD) of ash, organic matter, CP, fat, carbohydrates, starch and non-starch polysaccharides (NSP) divided into cellulose and soluble and insoluble non-cellulosic polysaccharide residues were measured using chromic oxide as marker. The recovery of total solid materials, organic matter and total carbohydrates in ileal digesta in pigs fed the HF and HFS diets was higher than in pigs fed LF and HFI, whereas recovery of organic matter and total carbohydrates in faecal materials in the HFS diet was lowest (P < 0.05). AID of organic matter, total carbohydrates and starch was lowest for HFS diet (P < 0.05). ATTD of organic matter and CP was higher for LF diet compared with other diets (P < 0.05), whereas total NSP, cellulose and non-cellulosic polysaccharides residues were highest for HFS diet (P < 0.05). Lactic acid in ileal digesta was influenced by dietary composition (P < 0.05) whereas neither type nor level of DF affected short chain fatty acids. The digestible energy, metabolisable energy, net energy and retained energy intake were similar among diets without influence of DF inclusion (P > 0.05). The metabolisable energy:digestible energy ratio was lower when feeding the HFS diet because of a higher fermentative methane loss. Faecal nitrogen and carbon were positively correlated with DM intake and insoluble DF in the diets (P < 0.05), but nitrogen and carbon (% of intake) were similar among diets. The present findings suggest that high-DF co-products can be used as ingredients of pig diets when features of DF are considered.

Detection of companion galaxies around hot dust-obscured hyper-luminous galaxy W0410-0913.

The phase transition between galaxies and quasars is often identified with the rare population of hyper-luminous, hot dust-obscured galaxies. Galaxy formation models predict these systems to grow via mergers, that can deliver large amounts of gas toward their centers, induce intense bursts of star formation and feed their supermassive black holes. Here we report the detection of 24 galaxies emitting Lyman-α emission on projected physical scales of about 400 kpc around the hyper-luminous hot dust-obscured galaxy W0410-0913, at redshift z = 3.631, using Very Large Telescope observations. While this indicates that W0410-0913 evolves in a very dense environment, we do not find clear signs of mergers that could sustain its growth. Data suggest that if mergers occurred, as models expect, these would involve less massive satellites, with only a moderate impact on the internal interstellar medium of W0410-0913, which is sustained by a rotationally-supported fast-rotating molecular disk, as Atacama Large Millimeter Array observations suggest.

Deep brain stimulation of the posterior hypothalamic area in intractable short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT).

BACKGROUND: SUNCT (short-lasting unilateral neuralgiform headache with conjunctival injection and tearing) is a rare syndrome characterized by the sudden onset of excruciating unilateral periorbital pain that is accompanied by conjunctival injection and lacrimation or further autonomic signs. Similar to patients with chronic cluster headache, Leone and Lyons showed a beneficial effect of deep brain stimulation of the posterior hypothalamic region in two patients with a chronic SUNCT. CASE: Here, we present the case of a man with a chronic SUNCT responding to deep brain stimulation of the posterior hypothalamic area. CONCLUSION: This case supports the idea of a central origin of SUNCT and shows that deep brain stimulation of the hypothalamic region can be effective in the treatment of the chronic form of this rare disorder.

Structuring from nanoparticles in oil-based ferrofluids.

The effect of magnetic field on the structure formation in an oil-based magnetic fluid with various concentrations of magnetite particles was studied. The evaluation of the experimental data obtained from small-angle X-ray scattering and ultrasonic attenuation indicates the formation of chain-like aggregates composed of magnetite particles. The experimental data obtained from ultrasonic spectroscopy fit well with the recent theoretical model by Shliomis, Mond and Morozov but only for a diluted magnetic fluid. In this model it is assumed that a dimer is the main building block of a B -field-induced chain-like structure, thus the estimation of the nematic order parameter does not depend on the actual length of the structure. The scattering method used reveals information about the aggregated structure size and relative changes in the degree of anisotropy in qualitative terms. The coupling constant [Formula: see text] , concentrations [Formula: see text] , average particle size d and its polydispersity [Formula: see text] were initially obtained using the vibrating sample magnetometry and these results were further confirmed by rheometry and scattering methods. Both the particles' orientational distribution and the nematic order parameter S were inferred from the ultrasonic measurements. The investigation of SAXS patterns reveals the orientation and sizes of aggregated structures under application of different magnetic-field strengths. In addition, the magnetic-field-dependent yield stress was measured, and a relationship between the yield stress and magnetic-field strength up to 0.5 T was established.

Genetic influence on the renin-angiotensin system. Evidence for a renin inhibitor in hypertension-prone rats.

TWO STRAINS OF RATS WITH OPPOSITE GENETIC PROPENSITY FOR HYPERTENSION WERE TESTED FOR: (a) the sensitivity to injections of angiotensin and renin, and (b) the influence of their plasma on the reaction velocity of renin and its substrate in vitro. Intact hypertension-prone (S) rats on low salt had higher sensitivity to angiotensin and a lower sensitivity to renin than hypertension-resistant (R) rats. High NaCl diet did not change the response of the R rats to these injections, but increased the response to renin and angiotensin in intact S rats. Bilateral nephrectomy caused increased response to renin and a decreased response to angiotensin in the S rats, so that both strains were equivalent after bilateral nephrectomy. In vitro, plasma from intact S rats inhibited the activity of hog renin. Plasma from R rats showed no inhibition. The inhibitor disappeared after bilateral nephrectomy. It was speculated that renin inhibitor may be involved in the development of hypertension by increasing sensitivity to angiotensin and other hypertensinogenic stimuli.

Effects of chronic excess salt ingestion. Genetic influence on the development of salt hypertension in parabiotic rats: evidence for a humoral factor.

Parabiosis has been found to modify the expected blood pressure response of rats from two strains with opposite genetic propensities for experimental hypertension. When a member from one strain was united in parabiosis with a member from the other and both were maintained on high NaCl diet, the rat from the strain ordinarily resistant to it rapidly developed hypertension, in contrast to appropriate controls from this strain. The development of hypertension in this resistant animal preceded that in its mate from the strain highly sensitive to hypertension. In the latter, both the level of hypertension and mortality were significantly less than in its control. It seems likely that the hypertension observed is the resistant parabiont was initiated in its partner from the sensitive strain. This modification in blood pressures was not observed in the absence of a high NaCl diet. Parabiosis between animals from the same strain did not alter their response. Thus, as in earlier experiences (1-4) the interaction of a nongenetic factor (NaCl) with the appropriate genetic substrate appeared to be necessary for the development of hypertension. The findings are interpreted as evidence that a transmittable humoral influence plays an important role in the pathogenesis of rat hypertension. The presence of this agent is genetically determined but, under the conditions of these experiments, it took the added stimulus of dietary NaCl to demonstrate its existence.

Effects of adrenalectomy on blood pressure in salt-fed, hypertension-prone rats. Failure of hypertension to develop in absence of evidence of adrenal cortical tissue.

In adrenalectomized, genetically hypertension-prone rats, a high degree of correlation was found between evidence of functioning adrenal tissue and the development of salt hypertension. There is considerable evidence that some rats have the capacity to regenerate functioning adrenal cortical tissue from accessory glands and microscopic rests, sometimes in remote locations. Therefore, the criteria for continued absence of adrenal function after surgical adrenalectomy are critical. In this study we used three tests to validate the presence, or absence, of adrenal function: (a) a biochemical test, the quantitative, serial measurement of plasma glucocorticoids in individual rats; (b) a physiological test, the ability to survive a virtually sodium-free diet; and (c) the anatomical search for histological evidence of adrenal cortical tissue. Among those animals that developed hypertension after adrenalectomy, the correlation between plasma steroid concentration and blood pressure was statistically significant. We suspect that this correlation exists only during the period when cortical tissue is regenerating; it does not exist among intact animals with and without hypertension induced by salt. It was concluded that some adrenocortical function is necessary for salt hypertension to develop. The evidence was insufficient to settle the question whether the action of corticosteroids is causative, or whether they play a supporting, although necessary, role for an extraadrenal hypertensinogenic factor to become manifest.

Genetic influence on the development of renal hypertension in parabiotic rats. Evidence for a humoral factor.

The effects of several renal manipulations including uninephrectomy, unilateral renal artery constriction, and a combination of these two (Goldblatt procedure) were studied in two strains of rats with opposite constitutional predispositions to experimental hypertension. The protective value of intact renal tissue to protect against hypertension was shown to be genetically determined. The Goldblatt procedure carried out on only one member of a parabiotic pair induced hypertension in this operated rat but significant hypertension developed in the intact partner only when the operated animal belonged to the strain predisposed to hypertension. It was speculated that there were qualitative differences in the pressor signals of the two strains of rats. In the strain genetically predisposed to hypertension there are at least two pressor principles: (a) one which is common to both strains, not transmittable via the parabiosis junction and presumably related to the renin-angiotensin system; and (b) a second which is specific for the hypertension-prone strain and can be transmitted through the parabiosis junction. This transmittable agent is probably identical with the factor that produces salt hypertension and is associated with the salt-excreting mechanism.