Subpolar North Atlantic western boundary density anomalies and the Meridional Overturning Circulation.

Changes in the Atlantic Meridional Overturning Circulation, which have the potential to drive societally-important climate impacts, have traditionally been linked to the strength of deep water formation in the subpolar North Atlantic. Yet there is neither clear observational evidence nor agreement among models about how changes in deep water formation influence overturning. Here, we use data from a trans-basin mooring array (OSNAP-Overturning in the Subpolar North Atlantic Program) to show that winter convection during 2014-2018 in the interior basin had minimal impact on density changes in the deep western boundary currents in the subpolar basins. Contrary to previous modeling studies, we find no discernable relationship between western boundary changes and subpolar overturning variability over the observational time scales. Our results require a reconsideration of the notion of deep western boundary changes representing overturning characteristics, with implications for constraining the source of overturning variability within and downstream of the subpolar region.

A sea change in our view of overturning in the subpolar North Atlantic.

To provide an observational basis for the Intergovernmental Panel on Climate Change projections of a slowing Atlantic meridional overturning circulation (MOC) in the 21st century, the Overturning in the Subpolar North Atlantic Program (OSNAP) observing system was launched in the summer of 2014. The first 21-month record reveals a highly variable overturning circulation responsible for the majority of the heat and freshwater transport across the OSNAP line. In a departure from the prevailing view that changes in deep water formation in the Labrador Sea dominate MOC variability, these results suggest that the conversion of warm, salty, shallow Atlantic waters into colder, fresher, deep waters that move southward in the Irminger and Iceland basins is largely responsible for overturning and its variability in the subpolar basin.

In situ biodistribution and residency of a topical anti-inflammatory using fluorescence lifetime imaging microscopy.

BACKGROUND: GSK2894512 is a topically delivered investigational drug being developed for treatment of atopic dermatitis and psoriasis. OBJECTIVES: To investigate, in a phase I clinical trial, the spatial biodistribution and residency of GSK2894512 within the epidermis and dermis of healthy human participants noninvasively using fluorescence lifetime imaging microscopy (FLIM). METHODS: Two topical drug formulations containing GSK2894512 1% were applied to the right and left forearms of six participants for seven consecutive days, followed by seven days of observation for residency. FLIM images were obtained daily throughout the study, approximately every 24 h. During the treatment phase of the study, images were collected from each participant pretreatment, reflecting the residual dose from the previous day. Three punch biopsies from each participant of one formulation was obtained from the treated region during the post-treatment follow-up period between days 8 and 14 for comparison with FLIM results. RESULTS: Cellular and subcellular features associated with different epidermal and dermal layers were visualized noninvasively, down to a depth of 200 µm. Results yielded three-dimensional maps of GSK2894512 spatial distribution and residency over time. This fluorescence data provided a marker that was used as a monitor for day-to-day variance of drug presence and residency postapplication. CONCLUSIONS: The results suggest FLIM could be a viable alternative to skin biopsies without the usual patient discomfort and limitations, thereby enabling the direct measurement of skin distribution through longitudinal monitoring. These results are the first step in establishing the unique capabilities that multiphoton imaging could provide to patients through noninvasive drug detection.

Teriparatide treatment patterns in osteoporosis and subsequent fracture events: a US claims analysis.

UNLABELLED: The objective of this study was to describe the risk of fragility-related fractures in the 2 years following teriparatide initiation. In an administrative claims analysis of over 11,407 patients, approximately one in eight patients had a new or recurrent fragility-related fracture in the 2 years following teriparatide initiation. INTRODUCTION: The objective of this study was to describe the risk of fragility-related fractures in the 2 years following the initiation of teriparatide in a real-world setting. METHODS: This retrospective study used data from the 2002 to 2011 MarketScan® Commercial and Medicare Supplemental Databases to identify patients 50 years and older with a diagnosis of osteoporosis (ICD-9-CM code 733.0x) who were initiating teriparatide. Patients were required to have continuous medical and pharmacy benefit coverage for the 12 months prior to and 24 months following teriparatide initiation (index event). Teriparatide treatment patterns (persistence and adherence) were described, as was the use of antiresorptive therapy. The primary study outcome was the presence of a new or recurring fragility fracture following the initiation of teriparatide. RESULTS: A total of 11,407 patients met the study criteria (mean age = 69.5, standard deviation = 10.6 years; 92.0% female). One in four (25.6%) patients had fragility fracture claims in the year prior to teriparatide initiation, of which 64.0% were on existing antiresorptive therapy. Overall, 13.4% (n = 1527) of patients had a new or recurrent fracture during the 2-year follow-up period. Forty-eight percent of patients on teriparatide treatment were considered persistent; fragility fractures were more common among patients nonpersistent with teriparatide (15.2%) than among those persistent with teriparatide (11.4%). A higher fracture rate (35.7%) was observed in the cohort with previous fragility fracture then those without pre-index fractures (24%). CONCLUSION: More than 13.4% of patients had new or recurrent fragility-related fractures during the 2 years following the initiation of teriparatide; these fractures were more in common in patients with pre-existing fractures and the patients who were nonpersistent with teriparatide.

Quantum-to-continuum prediction of ductility loss in aluminium-magnesium alloys due to dynamic strain aging.

Negative strain-rate sensitivity due to dynamic strain aging in Aluminium-5XXX alloys leads to reduced ductility and plastic instabilities at room temperature, inhibiting application of these alloys in many forming processes. Here a hierarchical multiscale model is presented that uses (i) quantum and atomic information on solute energies and motion around a dislocation core, (ii) dislocation models to predict the effects of solutes on dislocation motion through a dislocation forest, (iii) a thermo-kinetic constitutive model that faithfully includes the atomistic and dislocation scale mechanisms and (iv) a finite-element implementation, to predict the ductility as a function of temperature and strain rate in AA5182. The model, which contains no significant adjustable parameters, predicts the observed steep drop in ductility at room temperature, which can be directly attributed to the atomistic aging mechanism. On the basis of quantum inputs, this multiscale theory can be used in the future to design new alloys with higher ductility.

Patterns of treatment among a cohort of older low-income adults starting new medications for osteoporosis.

UNLABELLED: Among 125,954 new users of osteoporosis (OP) medications, 77 % of subjects stopped OP medications, and 23 % of subjects added or started a new OP medication during follow-up, with the first addition or start of a new OP medication occurring in a mean of 739 days after original OP treatment. INTRODUCTION: We described patterns and predictors of OP medication use, focusing on treatment changes over time. METHODS: We analyzed health and pharmacy insurance claims for a large cohort of low-income Medicare beneficiaries with a drug benefit for the years 1998-2008. Study subjects had documented Medicare claims and no receipt of OP medications (i.e., bisphosphonate, raloxifene, calcitonin, teriparatide, or hormonal therapy) during a baseline of 180 days. Subjects were then required to start an OP medication. Baseline patient and prescriber characteristics were assessed in multivariable Cox regression models to identify correlates of adding or starting a new OP medication. Fractures, bone mineral density testing, and visits with endocrinologists or rheumatologists occurring after baseline were also examined as correlates. RESULTS: We included 125,954 new users of OP medications with a mean age of 78 years, 97 % female, and 92 % white. OP medication prescribers included specialists (i.e., endocrinologists or rheumatologists) (6.2 %), orthopedic surgeons (1.0 %), primary care providers (64.9 %), other physicians (3.7 %), and missing (24.1 %). Seventy-seven percent of subjects stopped OP medications, and 23 % of subjects added or started a new OP medication during follow-up, with the first addition or start of a new OP medication occurring in a mean of 739 days after original OP treatment; 4 % added or started a new OP medication more than once. In fully adjusted models, many baseline variables correlated with starting a second OP medication. Post-baseline fractures [hazard ratio (HR) 1.76, 95 % confidence interval (CI) 1.71-1.82] and bone mineral density testing (HR 2.94, 95 % CI 2.86-3.03) were strong predictors. CONCLUSION: Approximately one quarter of patients starting an OP medication added or started a new OP medication during follow-up. Long-term sequential treatment strategy trials would inform optimal medication treatment for OP.

Unwinding of a strained cholesteric elastomer by disclination loop nucleation.

The application of a sufficiently strong strain perpendicular to the pitch axis of a monodomain cholesteric elastomer unwinds the cholesteric helix. Previous theoretical analyses of this transition ignored the effects of Frank elasticity which we include here. We find that the strain needed to unwind the helix is reduced because of the Frank penalty and the cholesteric state becomes metastable above the transition. We consider in detail a previously proposed mechanism by which the topologically stable helical texture is removed in the metastable state: namely, by the nucleation of twist disclination loops in the plane perpendicular to the pitch axis. We present an approximate calculation of the barrier energy for this nucleation process which neglects possible spatial variation of the strain fields in the elastomer, as well as a more accurate calculation based on a finite-element modeling of the elastomer.

Brain stem localization of neurons of the subdiaphragmatic vagus nerve fibres in the ferret (Mustela Putorius Furo): a WGA-HRP neurohistochemical study

The brain stem localization of neurons of nerve fibres in the ventral and dorsal abdominal vagal trunks were studied in the ferret. A total of 14 adult ferrets (six experimental and eight controls) were used for the study. Following anesthesia with pentobarbitone sodium, an upper midline laparotomy was done to expose the abdominal trunks of the vagus nerve. After dissecting the trunks clear of the abdominal oesophagus and the cardia of the stomach the nerve trunks were cut and WGA-HRP was applied to the proximal stump of the cut trunks. Control ferrets were divided into four groups of two ferrets. In the first group normal saline instead of the tracer was applied to the proximal stump of the vagal trunks. The second group was treated in a similar manner as the experimental animal except that the application of tracer was preceded by bilateral cervical vagotomy. In the third group of controls 0.1 ml of WGA-HRP was injected into the abdominal cavity and the fourth group had tracer injection into the hepatic portal vein. All animals were allowed a survival period of 48-72 hours after tracer injection following which each animal was perfused with normal saline, fixative and buffered sucrose. The brain stem was extracted and cut in transverse section (40 µm with the freezing microtome. Sections were then processed for WGA-HRP neurohistochemistry and subsequently viewed and analyzed under light/dark-field illuminations. In the experimental ferrets labeled cells were seen bilaterally in the dorsal motor nucleus of the vagus nerve (DMNV), the nucleus dorsomedialis (nDm), the nucleus ambiguus (nA) and the nucleus retroambiguus (nrA). The DMNV was the most intensely labeled nucleus. Sporadic distribution of labeled cells was also observed in the reticular formation (rf) between the nA and the DMNV. Labeled neurons were not seen in any of the control experiments.

Central Localisation of splenic preganglionic parsympathetic motorneurons; A wheat germ Agglutinatinin horse radish perioxidase (WGA-HRP) neurohistochemical study in the ferret (Mustela putorius furo).

Fourteen adult ferrets of both sexes and ranging in weight from 800-1500 gm were used in this investigation. Six of the ferrets were anaesthesized and a midline abdominal incision made to expose the spleen. With the aid of a Hamilton syringe and needle, the spleen of each ferret was injected with 0.1ml of 5% WGA-HRP in 0.5 M sodium chloride. The eight remaining ferrets were used as controls. Two of these had injections of 0.1ml normal saline into the spleen. The second set of two ferrets was injected with 0.1 ml of 5% WGA-HRP in buffer after bilateral trunkal vagotomy. The third set of two ferrets received intraperitoneal injection of 0.1ml of 5% WGA-HRP while in the last set the tracer was injected into the hepatic portal vein. Following the injections, the ferrets were allowed to survive for 48-72 hours after which each ferret was perfused transcardially with normal saline followed by a fixation containing paraformaldehyde and glutaraldehyde in phosphate buffer, pH 7.4 at room temperature and finally with 10% buffered sucrose at 4°C. After perfusion, the brainstem was extracted from the skull and immersed in 10% buffered sucrose and kept in the fridge overnight. Tranverse frozen sections of the brainstem were then taken, processed for WGA-HRP neurohistochemistry and analysed under light and dark field illuminations. Examination of the section taken from the six experimental ferrets revealed presence of WGA-HRP in neurons of the dorsal motor neurons in any brainstem nucleus.

Central Localisation of splenic preganglionic parsympathetic motorneurons; A wheat germ Agglutinatinin horse radish perioxidase (WGA-HRP) neurohistochemical study in the ferret (Mustela putorius furo).

Fourteen adult ferrets of both sexes and ranging in weight from 800-1500 gm were used in this investigation. Six of the ferrets were anaesthesized and a midline abdominal incision made to expose the spleen. With the aid of a Hamilton syringe and needle, the spleen of each ferret was injected with 0.1ml of 5% WGA-HRP in 0.5 M sodium chloride. The eight remaining ferrets were used as controls. Two of these had injections of 0.1ml normal saline into the spleen. The second set of two ferrets was injected with 0.1 ml of 5% WGA-HRP in buffer after bilateral trunkal vagotomy. The third set of two ferrets received intraperitoneal injection of 0.1ml of 5% WGA-HRP while in the last set the tracer was injected into the hepatic portal vein. Following the injections, the ferrets were allowed to survive for 48-72 hours after which each ferret was perfused transcardially with normal saline followed by a fixation containing paraformaldehyde and glutaraldehyde in phosphate buffer, pH 7.4 at room temperature and finally with 10% buffered sucrose at 4°C. After perfusion, the brainstem was extracted from the skull and immersed in 10% buffered sucrose and kept in the fridge overnight. Tranverse frozen sections of the brainstem were then taken, processed for WGA-HRP neurohistochemistry and analysed under light and dark field illuminations. Examination of the section taken from the six experimental ferrets revealed presence of WGA-HRP in neurons of the dorsal motor neurons in any brainstem nucleus.

The role of pressure in rubber elasticity.

We describe a series of molecular dynamics computations that reveal an intimate connection at the atomic scale between difference stress (which resists stretches) and pressure (which resists volume changes) in an idealized elastomer, in contrast to the classical theory of rubber elasticity. Our simulations idealize the elastomer as a "pearl necklace," in which the covalent bonds are stiff linear springs, while nonbonded atoms interact through a Lennard-Jones potential with energy epsilon(LJ) and radius sigma(LJ). We calculate the difference stress t(11)-(t(22)+t(33))/2 and mean stress (t(11)+t(22)+t(33))/3 induced by a constant volume extension in the x(1) direction, as a function of temperature T and reduced density rho(*)=Nsigma(IJ) (3)/nu. Here, N is the number of atoms in the simulation cell and nu is the cell volume. Results show that for rho(*)<1, the difference stress is purely entropic and is in good agreement with the classical affine network model of rubber elasticity, which neglects nonbonded interactions. However, data presented by van Krevelen [Properties of Polymers, 3rd ed. (Elsevier, Amsterdam, 1990), p. 79] indicate that rubber at standard conditions corresponds to rho(*)=1.2. For rho(*)>1, the system is entropic for kT/epsilon(LJ)>2, but at lower temperatures the difference stress contains an additional energy component, which increases as rho(*) increases and temperature decreases. Finally, the model exhibits a glass transition for rho(*)=1.2 and kT/epsilon(LJ) approximately 2. The atomic-scale processes responsible for generating stress are explored in detail. Simulations demonstrate that the repulsive portion of the Lennard-Jones potential provides a contribution sigma(nbr)>0 to the difference stress, the attractive portion provides sigma(nba) approximately 0, while the covalent bonds provide sigma(b)<0. In contrast, their respective contributions to the mean stress satisfy Pi(nbr)<0, Pi(nba)>0, and Pi(b)<0. Analytical calculations, together with simulations, demonstrate that mean and difference stresses are related by sigma(nbr)=-APi(nbr)P(2)(theta(b)), sigma(b)=BPi(b)P(2)(theta(b)), where P(2)(theta(b)) is a measure of the anisotropy of the orientation of the covalent bonds, and A and B are coefficients that depend weakly on rho(*) and temperature. For high values of rho(*), we find that [sigma(nbr)]>>[sigma(b)], and in this regime our model predicts behavior that is in good agreement with experimental data of D.L. Quested et al. [J. Appl. Phys. 52, 5977 (1981)] for the influence of pressure on the difference stress induced by stretching solithane.

Directly measured mid-depth circulation in the northeastern North Atlantic Ocean.

The circulation of water masses in the northeastern North Atlantic Ocean has a strong influence on global climate owing to the northward transport of warm subtropical water to high latitudes. But the ocean circulation at depths below the reach of satellite observations is difficult to measure, and only recently have comprehensive, direct observations of whole ocean basins been possible. Here we present quantitative maps of the absolute velocities at two levels in the northeastern North Atlantic as obtained from acoustically tracked floats. We find that most of the mean flow transported northward by the Gulf Stream system at the thermocline level (about 600 m depth) remains within the subpolar region, and only relatively little enters the Rockall trough or the Nordic seas. Contrary to previous work, our data indicate that warm, saline water from the Mediterranean Sea reaches the high latitudes through a combination of narrow slope currents and mixing processes. At both depths under investigation, currents cross the Mid-Atlantic Ridge preferentially over deep gaps in the ridge, demonstrating that sea-floor topography can constrain even upper-ocean circulation patterns.

BDNF and NT3 extend the critical period for developmental climbing fibre plasticity.

The effect on neonatal brain plasticity of two neurotrophins, brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), was studied using the rat olivocerebellar projection as a model. Unilateral transection of climbing fibres (CFs) in the rat before postnatal day 7 induces reinnervation of the deafferented hemicerebellum, but this does not occur if the transection is performed after postnatal day 10. Eleven-day-old day rats underwent unilateral CF transection followed by neurotrophin injection into the denervated cerebellar cortex 24 h later. The exogenous neurotrophins induced CF reinnervation of the denervated hemicerebellum. However BDNF was more efficacious than NT-3. Thus two neurotrophins can extend the window of neonatal brain plasticity, therefore suggesting potential therapeutic use after brain trauma.

Physiology of intra-abdominal and intrathoracic Nissen fundoplications in a porcine model.

BACKGROUND: The physiologic competency of intrathoracic fundoplications remains controversial. This study compared the physiologic qualities of intra-abdominal Nissen fundoplications (IAF) with those of intrathoracic Nissen fundoplications (ITF) in a porcine model. METHODS: The lower esophageal sphincter (LES) length (cm), LES resting pressure (mm Hg), and intragastric pressure (mm Hg) necessary to produce reflux or wrap distribution were manometrically assessed before and after IAF and ITF in 10 pigs. Mean +/- SD were compared using analysis of variance. RESULTS: There was no difference in LES length before and after IAF or ITF, but there was a significant increase in resting LES pressure after eithe

A comparison of common bile duct pressures after botulinum toxin injection into the sphincter of Oddi versus biliary stenting in a canine model.

BACKGROUND: Botulinum toxin A (Botox) functionally paralyzes the sphincter of Oddi in both animals and humans, resulting in reduced pressures. No study, however, has specifically addressed common bile duct (CBD) pressures after Botox injection into the sphincter of Oddi with regard to treating biliary leaks and fistulae. The goals of this present study are to compare, versus biliary stenting, the change in CBD pressures after Botox injection into the sphincter of Oddi, as well as to evaluate the timing of onset and duration of these effects on sphincteric relaxation. METHODS: After midline laparotomy in 20 mongrel dogs, a pediatric umbilical catheter was inserted into the CBD via a small cholecystotomy and attached to a water-perfused pressure transducer. After baseline CBD pressure readings, a lateral duodenotomy was performed. A total of 100 units of Botox was injected with an endoscopic sclerotherapy needle into all four quadrants of the ampulla. The dogs were randomly divided into four groups to undergo repeat laparotomy at either postoperative day 1 (group I), postoperative day 3 (group II), postoperative day 7 (group III), or postoperative day 14 (group IV). At the time of second laparotomy, a pressure-sensing catheter was reinserted into the CBD and pressures recorded. Each dog then underwent transpapillary biliary stenting with a 7 Fr. x 5 cm Cotton-Leung biliary stent and CBD pressures were again recorded. RESULTS: CBD pressures were significantly lower as compared with baseline for all groups after Botox injection and after biliary stenting (P <0.001) In addition, no significant differences in the degree of CBD pressure reduction were identified between groups I through IV after Botox injection. The measured decrease in CBD pressure from baseline after Botox injection as compared with biliary stenting was significantly different for groups I and II (P <0.05) but not for groups III and IV. CONCLUSION: Botox injection into the sphincter of Oddi results in significant CBD pressure reduction within 24 hours and continues for 14 days. Also, after postoperative day 3, there is no significant difference in the reduction of CBD pressure from baseline between Botox injection and biliary stenting. Based on these findings, Botox injection into the sphincter of Oddi may be a beneficial alternative to biliary stenting for the treatment of biliary leaks and fistulae.

Localization of low affinity nerve growth factor receptor in the rat inferior olivary complex during development and plasticity of climbing fibres.

The rat olivocerebellar pathway has a precise topography from an inferior olive (IOC) to Purkinje cells in the contralateral hemicerebellum. While its development and plasticity have been documented, the molecular mechanisms underlying these events are not fully elucidated. Neurotrophins are a family of growth factors with diverse roles in development and neuronal plasticity, acting through a two-receptor system, including a low affinity receptor (LNGFR) which binds all neurotrophins with similar affinity. Since neurotrophins are present in the cerebellum during early postnatal development when LNGFR is synthesized in the IOC, they may act as target-derived trophic agents for climbing fibres during development and plasticity. To assess this, standard immunohistochemistry was used to document the distribution of LNGFR in the rat IOC during climbing fibre development and until cerebellar development was complete at postnatal day 28 (P28). LNGFR immunoreactivity (LNGFR-IR) was detected in the IOC from P0 until P15, however after P7 it diminished in intensity and distribution, a change which indicates a relationship between cerebellar neurotrophins and climbing fibre development. After denervation of the left hemicerebellum, there was an apparent increase in inferior olivary LNGFR-IR that was concurrent with climbing fibre re-innervation. Thus the results of this study support the hypothesis that neurotrophins are involved in climbing fibre development and suggest a possible contribution to the plasticity of the olivocerebellar pathway.