K022: Effect of combination therapy (ANG II antagonist, valsartan and a calcium channel blocker) in a hypertensive model of diabetic nephropathy

Recently, it has been suggested that in the context of diabetes and hypertension, more aggressive blood pressure targets should be considered. To achieve these levels of blood pressure control, it is likely that combination therapy will need to be used. The present study has explored the role of the addition of either a dihydropyridine or a non-dihydropyridine calcium channel blocker (CCB) to Ang II antagonist based treatment in an experimental model of hypertension and diabetes. The doses chosen for the combination therapy groups were lower than those used with monotherapy in order to achieve similar antihypertensive efficacy. Diabetic (streptozotocin induced) SHR were randomised to no treatment, valsartan (30 mg/kg/day), the non-dihydropyridine CCB verapamil (20 mg/kg/day), the dihydropyridine CCB amlodipine (6 mg/kg/day), a combination of valsartan and amlodipine (20 mg + 4 mg/kg/day respectively) or valsartan and verapamil (20 mg + 15 mg/kg/day respectively). Serial measurements of systolic blood pressure (BP) and albumin excretion rate (AER) were performed monthly (data are shown at week 16 for AER and mean of wk 20-28 for BP). This model was associated with hypertension (control, 217 ± 8, diabetic, 200 ± 5 mmHg) which was reduced by most treatments to a similar degree (valsartan 165 ± 3, amlodipine 164 ± 2, verapamil 182 ± 4, valsartan + amlodipine 151 ± 3 and valsartan + verapamil 169 ± 5 mmHg). Diabetes was associated with a progressive increase in AER (control 1.5 vs diabetic 17 mg/24 hr). Valsartan retarded the increase in AER (11 mg/24 hr). Similar efficacy was observed in the valsartan + amlodipine combination (9 mg/24 hr) but not with amlodipine alone (16 mg/24 hr) despite similar effects on blood pressure. No advantage of verapamil versus amlodipine either as monotherapy or in combination with valsartan was observed. The present study indicates that the combination of an Ang II antagonist and a dihydropyridine CCB is an effective regimen at reducing blood pressure and albuminuria in the context of diabetes and hypertensio

Granular cell tumour of the tongue in a 17‐year‐old orthodontic patient: a case report

To describe the clinical presentation of a granular cell tumour ( GCT ) in an orthodontic patient, as well as discuss its aetiology and treatment of choice. We present a case of GCT of the tongue in an otherwise healthy 17‐year‐old male patient along with a brief review of literature on GCT s. The lesion was surgically excised and orthodontic treatment was successfully finalised. Clinically, GCTs are indistinguishable from other benign connective tissue and neural tissue neoplasms and may be found in any site, with cases commonly involving the gastrointestinal system, breast and lung. However, over 50% of cases involve the head and neck, with the tongue being the most frequently involved site (65–85% of oral GCTs ). GCTs demonstrate a close anatomical relationship with peripheral nerve fibres and demonstrate the presence of myelin and axon‐like structures thus lending credence to their neural origin. The treatment of choice for GCTs is conservative surgical excision. Because GCTs present with a potential for recurrence, follow‐up is recommended. While the primary focus of orthodontic treatment is the position of the teeth within the orofacial complex, the health and wellness of the patient and his/her surrounding oral tissues always take precedence. This case demonstrates the importance of routine physical examination of the intraoral and extraoral tissues during routine orthodontic care.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106806/1/ors12055.pd

Safety and tolerability of NXY-059 for acute intracerebral hemorrhage: the CHANT trial

<p><b>Background and Purpose:</b> NXY-059 is a free radical-trapping neuroprotectant developed for use in acute ischemic stroke. To facilitate prompt administration of treatment, potentially before neuroimaging, we investigated the safety of NXY-059 in patients with intracerebral hemorrhage (ICH).</p> <p><b>Methods:</b> We randomized 607 patients within 6 hours of acute ICH to receive 2270 mg intravenous NXY-059 over 1 hour and then up to 960 mg/h over 71 hours, or matching placebo, in addition to standard care. The primary outcome was safety: the mortality and the frequency of adverse events, and the change from baseline for a variety of serum, imaging, and electrophysiological measurements. We also studied the overall distribution of disability scores on the modified Rankin Scale (mRS) and the Barthel index.</p> <p><b>Results:</b> We treated 300 patients with NXY-059 and 303 with placebo. Treatment groups were well matched for prognostic variables including Glasgow Coma Scale, risk factors, and age. The mean National Institute of Health Stroke Scale score on admission was 14 in both groups. The baseline hemorrhage volume was 22.4±20.1 mL in the NXY-059 group and 23.3±22.8 mL in the placebo group (mean±SD). Most hemorrhages were related to hypertension or anticoagulant use. Mortality was similar in both groups: 20.3% for NXY-059 and 19.8% for placebo-treated patients. The proportion of patients who experienced an adverse event was the same for both groups, whereas for serious adverse events the proportion was slightly higher in the NXY-059 group. However, no pattern emerged to indicate a safety concern. Serum potassium fell transiently in both groups, lower in the NXY-059 group. There were no differences in 3-month function, disability, or neurological deficit scores. The odds ratio for an improved outcome in 3-month mRS scores in the NXY-059 group was 1.01 (95% CI 0.75, 1.35).</p> <p><b>Conclusions:</b> NXY-059 given within 6 hours of acute ICH has a good safety and tolerability profile, with no adverse effect on important clinical outcomes.</p&gt

3D seismic imaging of buried Younger Dryas mass movement flows: Lake Windermere, UK

Windermere is a glacially overdeepened lake located in the southeastern Lake District, UK. Using the threedimensional(3D) Chirp subbottom profiler, we image mass movement deposits related to the Younger Dryas(YD) within a decimetre-resolution 3D seismic volume, documenting their internal structure and interactionwith preexisting deposits in unprecedented detail. Three distinct flow events are identified and mappedthroughout the 3D survey area. Package structures and seismic attributes classify them as: a small (totalvolume of c. 1500 m3) debris flow containing deformed translated blocks; a large (inferred total volume ofc. 500,000 m3), homogeneous fine-grained mass flow deposit; and a debris flow (inferred total volume ofc. 60,000 m3) containing small (c. 8.0×2.0 m) deformed translated blocks. Geomorphological mapping oftheir distribution and interaction with preexisting sediments permit the reconstruction of a depositionalhistory for the stratigraphic units identified in the seismic volume.<br/

Large-Scale Structure at z~2.5

We have made a statistically complete, unbiased survey of C IV systems toward a region of high QSO density near the South Galactic Pole using 25 lines of sight spanning $1.5<z<2.8$. Such a survey makes an excellent probe of large-scale structure at early epochs. We find evidence for structure on the $15-35h^{-1}$ proper Mpc scale ($H_0 \equiv 100$ km $s^{-1}$ Mpc${-1}$) as determined by the two point C IV - C IV absorber correlation function, and reject the null hypothesis that C IV systems are distributed randomly on such scales at the $\sim 3.5\sigma$ level. The structure likely reflects the distance between two groups of absorbers subtending $\sim~ 13 \times 5 \times 21h^{-3}$ and $\sim 7 \times 1 \times 15h^{-3}$ Mpc$^3$ at $z\sim 2.3$ and $z \sim 2.5$ respectively. There is also a marginal trend for the association of high rest equivalent width C IV absorbers and QSOs at similar redshifts but along different lines of sight. The total number of C IV systems detected is consistent with that which would be expected based on a survey using many widely separated lines of sight. Using the same data, we also find 11 Mg II absorbers in a complete survey toward 24 lines of sight; there is no evidence for Mg II - Mg II or Mg II - QSO clustering, though the sample size is likely still small to detect such structure if it exists.Comment: 56 pages including 32 of figures, in gzip-ed uuencoded postscript format, 1 long table not included, aastex4 package. Accepted for publication in ApJ Supplement

Cryptic loxP sites in mammalian genomes: genome-wide distribution and relevance for the efficiency of BAC/PAC recombineering techniques

Cre is widely used for DNA tailoring and, in combination with recombineering techniques, to modify BAC/PAC sequences for generating transgenic animals. However, mammalian genomes contain recombinase recognition sites (cryptic loxP sites) that can promote illegitimate DNA recombination and damage when cells express the Cre recombinase gene. We have created a new bioinformatic tool, FuzznucComparator, which searches for cryptic loxP sites and we have applied it to the analysis of the whole mouse genome. We found that cryptic loxP sites occur frequently and are homogeneously distributed in the genome. Given the mammalian nature of BAC/PAC genomic inserts, we hypothesised that the presence of cryptic loxP sites may affect the ability to grow and modify BAC and PAC clones in E. coli expressing Cre recombinase. We have observed a defect in bacterial growth when some BACs and PACs were transformed into EL350, a DH10B-derived bacterial strain that expresses Cre recombinase under the control of an arabinose-inducible promoter. In this study, we have demonstrated that Cre recombinase expression is leaky in un-induced EL350 cells and that some BAC/PAC sequences contain cryptic loxP sites, which are active and mediate the introduction of single-strand nicks in BAC/PAC genomic inserts

Isoscalar dipole strength in ^{208}_{82}Pb_{126}: the spurious mode and the strength in the continuum

Isoscalar dipole (compression) mode is studied first using schematic harmonic-oscillator model and, then, the self-consistent Hartree-Fock (HF) and random phase approximation (RPA) solved in coordinate space. Taking ^{208}Pb and the SkM* interaction as a numerical example, the spurious component and the strength in the continuum are carefully examined using the sum rules. It is pointed out that in the continuum calculation one has to use an extremely fine radial mesh in HF and RPA in order to separate, with good accuracy, the spurious component from intrinsic excitations.Comment: 19 pages, 2 figure

Functional and molecular analysis of proprioceptive sensory neuron excitability in mice

Neurons located in dorsal root ganglia (DRG) are crucial for transmitting peripheral sensations such as proprioception, touch, temperature, and nociception to the spinal cord before propagating these signals to higher brain structures. To date, difficulty in identifying modality-specific DRG neurons has limited our ability to study specific populations in detail. As the calcium-binding protein parvalbumin (PV) is a neurochemical marker for proprioceptive DRG cells we used a transgenic mouse line expressing green fluorescent protein (GFP) in PV positive DRGs, to study the functional and molecular properties of putative proprioceptive neurons. Immunolabeled DRGs showed a 100% overlap between GFP positive (GFP+) and PV positive cells, confirming the PVeGFP mouse accurately labeled PV neurons. Targeted patch-clamp recording from isolated GFP+ and GFP negative (GFP−) neurons showed the passive membrane properties of the two groups were similar, however, their active properties differed markedly. All GFP+ neurons fired a single spike in response to sustained current injection and their action potentials (APs) had faster rise times, lower thresholds and shorter half widths. A hyperpolarization-activated current (Ih) was observed in all GFP+ neurons but was infrequently noted in the GFP− population (100% vs. 11%). For GFP+ neurons, Ih activation rates varied markedly, suggesting differences in the underlying hyperpolarization-activated cyclic nucleotide-gated channel (HCN) subunit expression responsible for the current kinetics. Furthermore, quantitative polymerase chain reaction (qPCR) showed the HCN subunits 2, 1, and 4 mRNA (in that order) was more abundant in GFP+ neurons, while HCN 3 was more highly expressed in GFP− neurons. Likewise, immunolabeling confirmed HCN 1, 2, and 4 protein expression in GFP+ neurons. In summary, certain functional properties of GFP+ and GFP− cells differ markedly, providing evidence for modality-specific signaling between the two groups. However, the GFP+ DRG population demonstrates considerable internal heterogeneity when hyperpolarization-activated cyclic nucleotide-gated channel (HCN channel) properties and subunit expression are considered. We propose this heterogeneity reflects the existence of different peripheral receptors such as tendon organs, muscle spindles or mechanoreceptors in the putative proprioceptive neuron population

Conserving and Gapless Approximations for an Inhomogeneous Bose Gas at Finite Temperatures

We derive and discuss the equations of motion for the condensate and its fluctuations for a dilute, weakly interacting Bose gas in an external potential within the self--consistent Hartree--Fock--Bogoliubov (HFB) approximation. Account is taken of the depletion of the condensate and the anomalous Bose correlations, which are important at finite temperatures. We give a critical analysis of the self-consistent HFB approximation in terms of the Hohenberg--Martin classification of approximations (conserving vs gapless) and point out that the Popov approximation to the full HFB gives a gapless single-particle spectrum at all temperatures. The Beliaev second-order approximation is discussed as the spectrum generated by functional differentiation of the HFB single--particle Green's function. We emphasize that the problem of determining the excitation spectrum of a Bose-condensed gas (homogeneous or inhomogeneous) is difficult because of the need to satisfy several different constraints.Comment: plain tex, 19 page

Ground state of a polydisperse electrorheological solid: Beyond the dipole approximation

The ground state of an electrorheological (ER) fluid has been studied based on our recently proposed dipole-induced dipole (DID) model. We obtained an analytic expression of the interaction between chains of particles which are of the same or different dielectric constants. The effects of dielectric constants on the structure formation in monodisperse and polydisperse electrorheological fluids are studied in a wide range of dielectric contrasts between the particles and the base fluid. Our results showed that the established body-centered tetragonal ground state in monodisperse ER fluids may become unstable due to a polydispersity in the particle dielectric constants. While our results agree with that of the fully multipole theory, the DID model is much simpler, which offers a basis for computer simulations in polydisperse ER fluids.Comment: Accepted for publications by Phys. Rev.