Black and White and Read All Over: Press Protection After Branzburg

In 1972, the Supreme Court handed the press an apparent resounding defeat in Branzburg v. Hayes, declaring that the Constitution provided reporters no privilege from testifying about their confidential sources. This Note uses previously unpublished materials from the Justices\u27 personal files to illustrate the behind-the-scenes deliberations as the Court shifted in ideology from the propress posture established by Justice Hugo Black in the Pentagon Papers case to the anti-privilege position established by Justice Byron White one year later in Branzburg. It also examines the curious concurring opinion of Justice Lewis Powell in Branzburg and subsequent efforts to craft a qualified reporter\u27s privilege, arguing against further weakening press protection

Postnatal β2 adrenergic treatment improves insulin sensitivity in lambs with IUGR but not persistent defects in pancreatic islets or skeletal muscle

Placental insufficiency causes intrauterine growth restriction (IUGR) and disturbances in glucose homeostasis with associated β adrenergic receptor (ADRβ) desensitization. Our objectives were to measure insulin-sensitive glucose metabolism in neonatal lambs with IUGR and to determine whether daily treatment with ADRβ2 agonist and ADRβ1/β3 antagonists for 1 month normalizes their glucose metabolism. Growth, glucose-stimulated insulin secretion (GSIS) and glucose utilization rates (GURs) were measured in control lambs, IUGR lambs and IUGR lambs treated with adrenergic receptor modifiers: clenbuterol atenolol and SR59230A (IUGR-AR). In IUGR lambs, islet insulin content and GSIS were less than in controls; however, insulin sensitivity and whole-bodyGUR were not different from controls.Of importance, ADRβ2 stimulation with β1/β3 inhibition increases both insulin sensitivity and whole-body glucose utilization in IUGR lambs. In IUGR and IUGR-AR lambs, hindlimb GURs were greater but fractional glucose oxidation rates and ex vivo skeletal muscle glucose oxidation rates were lower than controls. Glucose transporter 4 (GLUT4) was lower in IUGR and IUGR-AR skeletal muscle than in controls but GLUT1 was greater in IUGR-AR. ADRβ2, insulin receptor, glycogen content and citrate synthase activity were similar among groups. In IUGR and IUGR-AR lambs heart rates were greater, which was independent of cardiac ADRβ1 activation. We conclude that targeted ADRβ2 stimulation improved whole-body insulin sensitivity but minimally affected defects in GSIS and skeletal muscle glucose oxidation. We show that risk factors for developing diabetes are independent of postnatal catch-up growth in IUGR lambs as early as 1 month of age and are inherent to the islets and myocytes

A framework for synthesis of safety justification for digitally enabled healthcare services

Digitally enabled healthcare services combine socio-technical resources to deliver the required outcomes to patients. Unintended operation of these services may result in adverse effects to the patient. Eliminating avoidable harm requires a systematic way of analysing the causal conditions, identifying opportunities for intervention. Operators of such services may be required to justify, and communicate, their safety. For example, the UK Standardisation Committee for Care Information (SCCI) standards 0129 and 0160 require a safety justification for health IT (superseded versions were known as the Information Standards Board (ISB) 0129 & 0160. Initial as well as current standards are maintained by the NHS Digital.MethodA framework was designed, and applied as proof of concept, to an IT-supported clinical emergencies (A&E) service. Evaluation was done qualitatively based on the authors? experience, identifying potential benefits of the approach.ResultsThe applied framework encapsulates analysis, and structures the generated information, into a skeleton of an evidence-based case for safety. The framework improved management of the safety activities, assigning ownership to stakeholders (e.g. IT developer), also creating a clear and compelling safety justification.ConclusionsApplication of the framework significantly contributed to systematising an exploratory approach for analysing the service, in addition to existing methods such as reporting. Its application made the causal chain to harm more diaphanous. Constructing a safety case contributed to: (a) identifying potential assurance gaps, (b) planning production of information and evidence, and (c) communication of the justification by graphical unambiguous means

Islet Adaptations in Fetal Sheep Persist Following Chronic Exposure to High Norepinephrine

Complications in pregnancy elevate fetal norepinephrine (NE) concentrations. Previous studies in NE-infused sheep fetuses revealed that sustained exposure to high NE resulted in lower expression of α2-adrenergic receptors in islets and increased insulin secretion responsiveness after acutely terminating the NE infusion. In this study, we determined if the compensatory increase in insulin secretion following chronic elevation of NE is independent of hyperglycemia in sheep fetuses and whether it is persistent in conjunction with islet desensitization to NE. Following an initial assessment of glucose-stimulated insulin secretion (GSIS) at 129±1 days of gestation, fetuses were continuously infused for seven days with NE and maintained at euglycemia with a maternal insulin infusion. Fetal GSIS studies were again performed on days 8 and 12. Adrenergic sensitivity was determined in pancreatic islets collected at day 12. NE infusion increased (P\u3c0.01) fetal plasma NE concentrations and lowered (P\u3c0.01) basal insulin concentrations compared to vehicle-infused controls. GSIS was 1.8-fold greater (P\u3c0.05) in NE-infused fetuses compared to controls at both one and five days after discontinuing the infusion. Glucose-potentiated arginine-induced insulin secretion was also enhanced (P\u3c0.01) in NE-infused fetuses. Maximum GSIS in islets isolated from NE-infused fetuses was 1.6-fold greater (P\u3c0.05) than controls, but islet insulin content and intracellular calcium signaling were not different between treatments. The half-maximal inhibitory concentration for NE was 2.6-fold greater (P\u3c0.05) in NE-infused islets compared to controls. These findings show that chronic NE exposure and not hyperglycemia produce persistent adaptations in pancreatic islets that augment β-cell responsiveness in part through decreased adrenergic sensitivity

Lower extremity fatigue increases complexity of postural control during a single-legged stance

<p>Abstract</p> <p>Background</p> <p>Non-linear approaches to assessment of postural control can provide insight that compliment linear approaches. Control entropy (CE) is a recently developed statistical tool from non-linear dynamical systems used to assess the complexity of non-stationary signals. We have previously used CE of high resolution accelerometry in running to show decreased complexity with exhaustive exercise. The purpose of this study was to determine if complexity of postural control decreases following fatiguing exercise using CE.</p> <p>Methods</p> <p>Ten subjects (5 M/5 F; 25 ± 3 yr; 169.4 ± 11.7 cm; 79.0 ± 16.9 kg) consented to participation approved by Western Oregon University IRB and completed two trials separated by 2-7 days. Trials consisted of two single-legged balance tests separated by two Wingate anaerobic tests (WAnT; PreFat/PostFat), or rest period (PreRest/PostRest). Balance tests consisted of a series of five single-legged stances, separated by 30 s rest, performed while standing on the dominant leg for 15-s with the participant crossing the arms over the chest and flexing the non-dominant knee to 90 degrees. High resolution accelerometers (HRA) were fixed superficial to L3/L4 at the approximate center of mass (COM). Triaxial signals from the HRA were streamed in real time at 625 Hz. COM accelerations were recorded in g's for vertical (VT), medial/lateral (ML), and anterior/posterior (AP) axes. A newly developed statistic (R-test) was applied to group response shapes generated by Karhunen Loeve (KL) transform modes resulting from Control Entropy (CE) analysis.</p> <p>Results</p> <p>R-tests showed a significant mean vector difference (<it>p </it>< .05) within conditions, between axes in all cases, except PostFat, indicating the shape of the complexity response was different in these cases. R-test between conditions, within axis, differences were only present in PostFat for AP vs. PreFat (<it>p </it>< .05). T-tests showed a significantly higher overall CE PostFat in VT and ML compared to PreFat and PostRest (<it>p </it>< .0001). PostFat CE was also higher than PostRest in AP (<it>p </it>< .0001).</p> <p>Conclusions</p> <p>These data indicate that fatiguing exercise eliminates the differential complexity response between axes, but increases complexity in all axes compared to the non-fatigued condition. This has implications with regard to the effects of fatigue on strategies of the control system to maintain postural control.</p

Adrenal Demedullation and Oxygen Supplementation Independently Increase Glucose-Stimulated Insulin Concentrations in Fetal Sheep With Intrauterine Growth Restriction

In pregnancies complicated by placental insufficiency and intrauterine growth restriction (IUGR), fetal glucose and oxygen concentrations are reduced, whereas plasma norepinephrine and epinephrine concentrations are elevated throughout the final third of gestation. Here we study the effects of chronic hypoxemia and hypercatecholaminemia on β-cell function in fetal sheep with placental insufficiency-induced IUGR that is produced by maternal hyperthermia. IUGR and control fetuses underwent a sham (intact) or bilateral adrenal demedullation (AD) surgical procedure at 0.65 gestation. As expected, AD-IUGR fetuses had lower norepinephrine concentrations than intact-IUGR fetuses despite being hypoxemic and hypoglycemic. Placental insufficiency reduced fetal weights, but the severity of IUGR was less with AD. Although 2 basal plasma insulin concentrations were lower in intact-IUGR and AD-IUGR fetuses compared with intact-controls, glucose-stimulated insulin concentrations were greater in AD-IUGR fetuses compared with intact-IUGR fetuses. Interestingly, AD-controls had lower glucose- and arginine-stimulated insulin concentrations than intact-controls, but AD-IUGR and AD-control insulin responses were not different. To investigate chronic hypoxemia in the IUGR fetus, arterial oxygen tension was increased to normal levels by increasing the maternal inspired oxygen fraction. Oxygenation of IUGR fetuses enhanced glucose-stimulated insulin concentrations 3.3-fold in intact-IUGR and 1.7-fold in AD-IUGR fetuses but did not lower norepinephrine and epinephrine concentrations. Together these findings show that chronic hypoxemia and hypercatecholaminemia have distinct but complementary roles in the suppression of β-cell responsiveness in IUGR fetuses. Placental insufficiency restricts the supply of oxygen and nutrients to the fetus and causes intrauterine growth restriction (IUGR) (1, 2). The resulting fetal hypoxemia and hypoglycemia provoke endocrine responses that lower plasma insulin concentrations (3,–5). High norepinephrine and epinephrine concentrations are a hallmark of both human and animal IUGR fetuses (6,–11). These high concentrations of catecholamines inhibit insulin secretion from pancreatic β-cells and may contribute to very low insulin concentrations in the IUGR fetus (12, 13). In addition, chronic elevation of norepinephrine has been shown to slow fetal growth and induce asymmetric growth of fetal tissues (14, 15)

Fragmentation of a Circular Disc by Impact on a Frictionless Plate

The break-up of a two-dimensional circular disc by normal and oblique impact on a hard frictionless plate is investigated by molecular dynamics simulations. The disc is composed of numerous unbreakable randomly shaped convex polygons connected together by simple elastic beams that break when bent or stretched beyond a certain limit. It is found that for both normal and oblique impacts the crack patterns are the same and depend solely on the normal component of the impact velocity. Analysing the pattern of breakage, amount of damage, fragment masses and velocities, we show the existence of a critical velocity which separates two regimes of the impact process: below the critical point only a damage cone is formed at the impact site (damage), cleaving of the particle occurs at the critical point, while above the critical velocity the disc breaks into several pieces (fragmentation). In the limit of very high impact velocities the disc suffers complete disintegration (shattering) into many small fragments. In agreement with experimental results, fragment masses are found to follow the Gates-Gaudin-Schuhmann distribution (power law) with an exponent independent of the velocity and angle of impact. The velocity distribution of fragments exhibit an interesting anomalous scaling behavior when changing the impact velocity and the size of the disc.Comment: submitted to J. Phys: Condensed Matter special issue on Granular Medi

Postnatal β2 adrenergic treatment improves insulin sensitivity in lambs with IUGR but not persistent defects in pancreatic islets or skeletal muscle

Placental insufficiency causes intrauterine growth restriction (IUGR) and disturbances in glucose homeostasis with associated β adrenergic receptor (ADRβ) desensitization. Our objectives were to measure insulin-sensitive glucose metabolism in neonatal lambs with IUGR and to determine whether daily treatment with ADRβ2 agonist and ADRβ1/β3 antagonists for 1 month normalizes their glucose metabolism. Growth, glucose-stimulated insulin secretion (GSIS) and glucose utilization rates (GURs) were measured in control lambs, IUGR lambs and IUGR lambs treated with adrenergic receptor modifiers: clenbuterol atenolol and SR59230A (IUGR-AR). In IUGR lambs, islet insulin content and GSIS were less than in controls; however, insulin sensitivity and whole-bodyGUR were not different from controls.Of importance, ADRβ2 stimulation with β1/β3 inhibition increases both insulin sensitivity and whole-body glucose utilization in IUGR lambs. In IUGR and IUGR-AR lambs, hindlimb GURs were greater but fractional glucose oxidation rates and ex vivo skeletal muscle glucose oxidation rates were lower than controls. Glucose transporter 4 (GLUT4) was lower in IUGR and IUGR-AR skeletal muscle than in controls but GLUT1 was greater in IUGR-AR. ADRβ2, insulin receptor, glycogen content and citrate synthase activity were similar among groups. In IUGR and IUGR-AR lambs heart rates were greater, which was independent of cardiac ADRβ1 activation. We conclude that targeted ADRβ2 stimulation improved whole-body insulin sensitivity but minimally affected defects in GSIS and skeletal muscle glucose oxidation. We show that risk factors for developing diabetes are independent of postnatal catch-up growth in IUGR lambs as early as 1 month of age and are inherent to the islets and myocytes

Drug discovery for male subfertility using high-throughput screening:a new approach to an unsolved problem

STUDY QUESTIONCan pharma drug discovery approaches be utilized to transform investigation into novel therapeutics for male infertility?SUMMARY ANSWERHigh-throughput screening (HTS) is a viable approach to much-needed drug discovery for male factor infertility.WHAT IS KNOWN ALREADYThere is both huge demand and a genuine clinical need for new treatment options for infertile men. However, the time, effort and resources required for drug discovery are currently exorbitant, due to the unique challenges of the cellular, physical and functional properties of human spermatozoa and a lack of appropriate assay platform.STUDY DESIGN, SIZE, DURATIONSpermatozoa were obtained from healthy volunteer research donors and subfertile patients undergoing IVF/ICSI at a hospital-assisted reproductive techniques clinic between January 2012 and November 2016.PARTICIPANTS/MATERIALS, SETTING, METHODSA HTS assay was developed and validated using intracellular calcium ([Ca2+]i) as a surrogate for motility in human spermatozoa. Calcium fluorescence was detected using a Flexstation microplate reader (384-well platform) and compared with responses evoked by progesterone, a compound known to modify a number of biologically relevant behaviours in human spermatozoa. Hit compounds identified following single point drug screen (10 μM) of an ion channel-focussed library assembled by the University of Dundee Drug Discovery Unit were rescreened to ensure potency using standard 10 point half-logarithm concentration curves, and tested for purity and integrity using liquid chromatography and mass spectrometry. Hit compounds were grouped by structure activity relationships and five representative compounds then further investigated for direct effects on spermatozoa, using computer-assisted sperm assessment, sperm penetration assay and whole-cell patch clamping.MAIN RESULTS AND THE ROLE OF CHANCEOf the 3242 ion channel library ligands screened, 384 compounds (11.8%) elicited a statistically significant increase in calcium fluorescence, with greater than 3× median absolute deviation above the baseline. Seventy-four compounds eliciting ≥50% increase in fluorescence in the primary screen were rescreened and evaluated further, resulting in 48 hit compounds that produced a concentration-dependent increase in [Ca2+]i. Sperm penetration studies confirmed in vitro exposure to two hit compounds (A and B) resulted in significant improvement in functional motility in spermatozoa from healthy volunteer donors (A: 1 cm penetration index 2.54, 2 cm penetration index 2.49; P &lt; 0.005 and B: 1 cm penetration index 2.1, 2 cm penetration index 2.6; P &lt; 0.005), but crucially, also in patient samples from those undergoing fertility treatment (A: 1 cm penetration index 2.4; P = 0.009, 2 cm penetration index 3.6; P = 0.02 and B: 1 cm penetration index 2.2; P = 0.0004, 2 cm penetration index 3.6; P = 0.002). This was primarily as a result of direct or indirect CatSper channel action, supported by evidence from electrophysiology studies of individual sperm.LIMITATIONS, REASONS FOR CAUTIONIncrease and fluxes in [Ca2+]i are fundamental to the regulation of sperm motility and function, including acrosome reaction. The use of calcium signalling as a surrogate for sperm motility is acknowledged as a potential limitation in this study.WIDER IMPLICATIONS OF THE FINDINGSWe conclude that HTS can robustly, efficiently, identify novel compounds that increase [Ca2+]i in human spermatozoa and functionally modify motility, and propose its use as a cornerstone to build and transform much-needed drug discovery for male infertility.</p