Control of water intake by a pathway from the nucleus of the solitary tract to the paraventricular hypothalamic nucleus.

Several brain areas have been shown to participate in thirst and control of fluid intake. An understanding of how these circuits interact, and their roles in the activation, maintenance, and termination of fluid intake remains incomplete. Central glucagon-like peptide-1 (GLP-1) receptor activation appears to be an important part of the termination of drinking, but the site(s) of action for this suppression has not yet been determined. In an attempt to use GLP-1 responsiveness as a means to screen targets of hindbrain cells that participate in the termination of thirst and the resultant water intake, we injected the GLP-1 receptor agonist exendin-4 (Ex-4) into three brain areas known to express GLP-1 receptors, and measured subsequent water intake. Ex-4 reduced water consumption when injected into the paraventricular hypothalamic nucleus (PVH) and nucleus of the solitary tract (NTS), but not when injected into the nucleus accumbens (NAc). Using the effective response after injection into the PVH as a guide, we examined the connection between the NTS - the site of endogenous central GLP-1 production - and the PVH. Retrograde tracing combined with Fos immunohistochemistry suggested intake-induced activity in PVH-projecting NTS cells. To test the hypothesis that this pathway is important in the termination of drinking, we chemogenetically activated PVH-projecting hindbrain cells. Interestingly, activation of this population of cells increased water intake, calling into question the heterogeneity of the pathway with respect to the control of fluid intake. Taken together, we conclude that the PVH is a site of action for GLP-1 receptor activation in the inhibition of water intake, but suspect that endogenous GLP-1 in NTS-to-PVH projections may be counterbalanced by a parallel pathway that either activates or maintains already activated water intake.

Mixed Solid and Cystic Mass in an Infant.

Desmoplastic infantile tumors are rare supratentorial brain tumors that occur in pediatric patients. Desmoplastic infantile tumors are made up of 2 subtypes: desmoplastic infantile gangliogliomas and desmoplastic infantile astrocytomas. Desmoplastic infantile tumors are often identifiable on imaging on the basis of multiple characteristics. Nevertheless, pathologic analysis is required to confirm the diagnosis, particularly when the imaging features are atypical. Here, the radiology findings, surgical approach and subsequent management, and pathology of a desmoplastic infantile ganglioglioma are described.

Transport of solid bodies along tubular membrane tethers.

We study the crucial role of membrane fluctuations in maintaining a narrow gap between a fluid membrane tube and an enclosed solid particle. Solvent flows can occur in this gap, hence giving rise to a finite particle mobility along the tube. While our study has relevance for how cells are able to transport large organelles or other cargo along connecting membrane tubes, known as tunneling nanotubes, our calculations are also framed so that they can be tested by a specific in vitro experiment: A tubular membrane tether can be pulled from a membrane reservoir, such as an aspirated Giant Unilamellar Vesicle (GUV), e.g. using a conjugated bead that binds to the membrane and is held in a laser trap. We compute the subsequent mobility of colloidal particles trapped in the tube, focusing on the case when the particle is large compared to the equilibrium tube radius. We predict that the particle mobility should scale as ∼ σ-2/3, with σ the membrane tension.

Linear rheology as a potential monitoring tool for sputum in patients with Chronic Obstructive Pulmonary Disease (COPD).

BACKGROUND: The rheological properties of sputum may influence lung function and become modified in disease. OBJECTIVE: This study aimed to correlate the viscoelastic properties of sputum with clinical data on the severity of disease in patients with chronic obstructive pulmonary disease (COPD). METHODS: Sputum samples from COPD patients were investigated using rheology, simple mathematical modelling and Scanning Electron Microscopy (SEM). The samples were all collected from patients within two days of their admission to Prince Philip Hospital due to an exacerbation of their COPD. Oscillatory and creep rheological techniques were used to measure changes in viscoelastic properties at different frequencies over time. RESULTS: COPD sputum was observed to behave as a viscoelastic solid at all frequencies studied. Comparing the rheology of exacerbated COPD sputum with healthy sputum (not diagnosed with a respiratory disease) revealed significant differences in response to oscillatory shear and creep-recovery experiments, which highlights the potential clinical benefits of better understanding sputum viscoelasticity. A common power law model G(t)=G0(tτ0)-m was successfully fitted to experimental rheology data over the range of frequencies studied. CONCLUSIONS: A comparison between clinical data and the power law index m obtained from rheology, suggested that an important possible future application of this parameter is as a potential biomarker for COPD severity.

A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas.

Background: Soft tissue sarcomas (STSs) overexpress vascular endothelial growth factors (VEGF) and VEGF-receptors (VEGFR) activation have been associated with tumor aggressiveness. Tivozanib is a potent small molecule tyrosine kinase inhibitor against VEGFR1-3, with activity against PDGFRα/ß and cKIT. The primary endpoint of this study was progression free survival (PFS) rate at 16 weeks. Secondary end points were overall survival (OS), response rate, safety and correlative studies. Patients and methods: A Simon two-stage phase II trial was performed using tivozanib given orally at 1.5 mg daily, 3 week on 1 week off on a 28 day cycle until disease progression or intolerable toxicity. Results: Fifty-eight patients were enrolled and treated with tivozanib. Leiomyosarcoma was the most common STS histological type in our cohort (47%) and 27 patients (46%) had received at least 3 lines of therapy prior to study entry. Up to 24 patients (41%) had prior VEGF targeted therapies. Partial response and stable disease were observed in 2 (3.6%) and 30 (54.5%) patients. The 16 week PFS rate was 36.4% [95% confidence interval (CI) 23.7-49.1] and a median PFS of 3.5 months (95% CI 1.8-3). Median OS observed was 12.2 months (95% CI 8.1-16.8). The most frequent all grade toxicities were fatigue (48.3%), hypertension (43.1%), nausea (31%) and diarrhea (27.6%). The most common grade three toxicity was hypertension (22.4%). Correlative studies demonstrate no correlation between the expression of VEGFR 1, 2 or 3, PDGFRα/ß or FGF, and activity of tivozanib. Conclusion: Tivozanib was well tolerated and showed antitumor activity with a promising median PFS and PFS rate at 4 months in a heavily pretreated population of metastatic STSs. Our results support further studies to assess the clinical efficacy of tivozanib in STS. Clinical Trial Number: NCT01782313.

Curvature correction to the mobility of fluid membrane inclusions.

Using rigorous low-Reynolds-number hydrodynamic theory on curved surfaces, we provide, via a Stokeslet-type approach, a general and concise expression for the leading-order curvature correction to the canonical, planar, Saffman-Delbrück value of the diffusion constant for a small inclusion embedded in an arbitrarily (albeit weakly) curved fluid membrane. In order to demonstrate the efficacy and utility of this general result, we apply our theory to the specific case of calculating the diffusion coefficient of a locally curvature inducing membrane inclusion. By including both the effects of inclusion and membrane elasticity, as well as their respective thermal shape fluctuations, excellent agreement is found with recently published experimental data on the surface tension dependent mobility of membrane bound inclusions.

Early Biomarkers from Conventional and Delayed-Contrast MRI to Predict the Response to Bevacizumab in Recurrent High-Grade Gliomas.

BACKGROUND AND PURPOSE: The interpretation of the radiologic response of bevacizumab-treated patients with recurrent high-grade gliomas represents a unique challenge. Delayed-contrast MR imaging was recently introduced for calculating treatment-response-assessment maps in patients with brain tumors, providing clear separation between active tumor and treatment effects. We studied the application of standard and delayed-contrast MR imaging for assessing and predicting the response to bevacizumab. MATERIALS AND METHODS: Twenty-four patients with recurrent high-grade gliomas were scanned before and during bevacizumab treatment by standard and delayed-contrast MR imaging. The mean change in lesion volumes of responders (overall survival, ≥1 year) and nonresponders (overall survival, <1 year) was studied. The lesion volumes at baseline and the changes in lesion volumes 1 month after treatment initiation, calculated from standard and delayed-contrast MRIs, were studied as possible predictors of outcome. In scans acquired at progression, the average change in lesion volume from previous follow-up in standard and delayed-contrast MRIs was compared. RESULTS: Response and progression patterns were identified from the mean change in lesion volumes, depicted from conventional T1WI, delayed contrast-enhanced MR imaging, and DSC MR imaging. Thresholds for early prediction of response were calculated by using these sequences. For each predictor, sensitivity, specificity, positive predictive values, and negative predictive values were calculated, reaching 85.7%, 87.5%, 75%, and 93.3% for conventional T1WI; 100%, 87.5%, 77.8%, and 100% for delayed-contrast MR imaging; and 75%, 78.6%, 50%, and 91.7% for DSC MR imaging. The benefit of delayed-contrast MR imaging in separating responders and nonresponders was further confirmed by using log-rank tests (conventional T1WI, P = .0022; delayed-contrast MR imaging, P < .0001; DSC MR imaging, P = .0232) and receiver operating characteristic analyses. At progression, the increase in lesion volumes in delayed-contrast MR imaging was 37.5% higher than the increase in conventional T1WI (P < .01); these findings suggest that progression may be depicted more effectively in treatment-response-assessment maps. CONCLUSIONS: The benefit of contrast-enhanced MR imaging for assessing and predicting the response to bevacizumab was demonstrated. The increased sensitivity of the treatment-response-assessment maps reflects their potential contribution to the management of bevacizumab-treated patients with recurrent high-grade glioma.

Moxonidine into the lateral parabrachial nucleus modifies postingestive signals involved in sodium intake control.

The activation of α2-adrenoceptors with bilateral injections of moxonidine (α2-adrenoceptor and imidazoline receptor agonist) into the lateral parabrachial nucleus (LPBN) increases 1.8% NaCl intake induced by treatment with furosemide (FURO)+captopril (CAP) subcutaneously. In the present study, we analyzed licking microstructure during water and 1.8% NaCl intake to investigate the changes in orosensory and postingestive signals produced by moxonidine injected into the LPBN. Male Sprague-Dawley rats were treated with FURO+CAP combined with bilateral injections of vehicle or moxonidine (0.5 nmol/0.2 µl) into the LPBN. Bilateral injections of moxonidine into the LPBN increased FURO+CAP-induced 1.8% NaCl intake, without changing water intake. Microstructural analysis of licking behavior found that this increase in NaCl intake was a function of increased number of licking bursts from 15 to 75 min of the test (maximum of 49±9 bursts/bin, vs. vehicle: 2±2 bursts/bin). Analysis of the first 15 min of the test, when most of the licking behavior occurred, found no effect of moxonidine on the number of licks/burst for sodium intake (24±5 licks/burst, vs. vehicle: 27±8 licks/burst). This finding suggests that activation of α2-adrenoceptors in the LPBN affects postingestive signals that are important to inhibit and limit sodium intake by FURO+CAP-treated rats.

Enhanced consumption of salient solutions following pedunculopontine tegmental lesions.

Rats with lesions of the pedunculopontine tegmental nucleus (PPTg) reliably overconsume high concentration sucrose solution. This effect is thought to be indicative of response-perseveration or loss of behavioral control in conditions of high excitement. While these theories have anatomical and behavioral support, they have never been explicitly tested. Here, we used a contact lickometer to examine the microstructure of drinking behavior to gain insight into the behavioral changes during overconsumption. Rats received either excitotoxic (ibotenic acid) damage to all PPTg neuronal subpopulations or selective depletion of the cholinergic neuronal sub-population (diphtheria toxin-urotensin II (Dtx-UII) lesions). We offered rats a variety of pleasant, neutral and aversive tastants to assess the generalizability and specificity of the overconsumption effect. Ibotenic-lesioned rats consumed significantly more 20% sucrose than sham controls, and did so through licking significantly more times. However, the behavioral microstructure during overconsumption was unaffected by the lesion and showed no indications of response-perseveration. Furthermore, the overconsumption effect did not generalize to highly consumed saccharin. In contrast, while only consuming small amounts of quinine solution, ibotenic-lesioned rats had significantly more licks and bursts for this tastant. Selective depletion of cholinergic PPTg neurons had no effect on consumption of any tastant. We then assessed whether it is the salience of the solution which determines overconsumption by ibotenic-lesioned rats. While maintained on free-food, ibotenic-lesioned rats had normal consumption of sucrose and hypertonic saline. After mild food deprivation ibotenic PPTg-lesioned rats overconsumed 20% sucrose. Subsequently, after dietary-induced sodium deficiency, lesioned rats consumed significantly more saline than controls. These results establish that it is the salience of the solution which is the determining factor leading to overconsumption following excitotoxic PPTg lesion. They also find no support for response-perseveration contributing to this effect. Results are discussed in terms of altered dopamine (DA) and salience signaling.

Highly sensitive covalently functionalised integrated silicon nanowire biosensor devices for detection of cancer risk biomarker.

In this article we present ultra-sensitive, silicon nanowire (SiNW)-based biosensor devices for the detection of disease biomarkers. An electrochemically induced functionalisation method has been employed to graft antibodies targeted against the prostate cancer risk biomarker 8-hydroxydeoxyguanosine (8-OHdG) to SiNW surfaces. The antibody-functionalised SiNW sensor has been used to detect binding of the 8-OHdG biomarker to the SiNW surface within seconds of exposure. Detection of 8-OHdG concentrations as low as 1 ng/ml (3.5 nM) has been demonstrated. The active device has been bonded to a disposable printed circuit which can be inserted into an electronic readout system as part of an integrated Point of Care (POC) diagnostic. The speed, sensitivity and ease of detection of biomarkers using SiNW sensors render them ideal for eventual POC diagnostics.

Glucagon-like peptide-1 receptor agonist administration suppresses both water and saline intake in rats.

Glucagon-like peptide-1 (GLP-1) plays an important role in energy homeostasis. Injections of GLP-1 receptor (GLP-1R) agonists suppress food intake, and endogenous GLP-1 is released when nutrients enter the gut. There is also growing evidence that the GLP-1 system is involved in the regulation of body fluid homeostasis. GLP-1R agonists suppress water intake independent of their effects on food intake. It is unknown, however, whether this suppressive effect of GLP-1R agonists extends to saline intake. Accordingly, we tested the effect of the GLP-1R agonists liraglutide (0.05 µg) and exendin-4 (0.05 µg) on water and saline intake, as stimulated either by angiotensin II (AngII) or by water deprivation with partial rehydration (WD-PR). Each agonist suppressed AngII-induced water intake; however, only exendin-4 suppressed saline intake. WD-PR-induced water and saline intakes were both attenuated by each agonist. Analysis of drinking microstructure after WD-PR found a reliable effect of the agonists on burst number. Furthermore, exendin-4 conditioned a robust taste avoidance to saccharine; however, there was no similar effect of liraglutide. To evaluate the relevance of the conditioned taste avoidance, we tested whether inducing visceral malaise by injection of lithium chloride (LiCl) suppressed fluid intake. Injection of LiCl did not suppress water or saline intakes. Overall, these results indicate that the fluid intake suppression by GLP-1R activation is not selective to water intake, is a function of post-ingestive feedback, and is not secondary to visceral malaise.

Islands of conformational stability for filopodia.

Filopodia are long, thin protrusions formed when bundles of fibers grow outwardly from a cell surface while remaining closed in a membrane tube. We study the subtle issue of the mechanical stability of such filopodia and how this depends on the deformation of the membrane that arises when the fiber bundle adopts a helical configuration. We calculate the ground state conformation of such filopodia, taking into account the steric interaction between the membrane and the enclosed semiflexible fiber bundle. For typical filopodia we find that a minimum number of fibers is required for filopodium stability. Our calculation elucidates how experimentally observed filopodia can obviate the classical Euler buckling condition and remain stable up to several tens of µm. We briefly discuss how experimental observation of the results obtained in this work for the helical-like deformations of enclosing membrane tubes in filopodia could possibly be observed in the acrosomal reactions of the sea cucumber Thyone, and the horseshoe crab Limulus. Any realistic future theories for filopodium stability are likely to rely on an accurate treatment of such steric effects, as analysed in this work.

UK national re-audit of sexual history-taking.

A focused repeat national audit of sexual history-taking was conducted in genitourinary (GU) medicine clinics in the UK in 2010, addressing several areas of practice under-performance identified in the baseline 2008 national audit. The case-notes of 4285 patients were audited. An increase in documentation was observed for all measures, except legibility which was unchanged. Despite the overall improvement, several measures (chaperone offer, condom usage and four of five aspects of HIV risk assessment) remained below target.

Ukrain, a plant derived semi-synthetic compound, exerts antitumor effects against murine and human breast cancer and induce protective antitumor immunity in mice.

UNLABELLED: Despite the recent advances in anti-cancer therapies, breast cancer accounts for the highest percentage of estimated new cases among female cancer patients. The anti-cancer drug Ukrain, a plant-derived semi-synthetic compound, has been shown to be effective in a variety of tumor models including colon, brain, ovarian, melanoma and lymphoma. However, the direct cytotoxic effects of Ukrain have yet to be investigated in breast cancer models. AIM: Herein, we investigated the in vitro and in vivo cytotoxicity of Ukrain using murine (4T07 and TUBO) and human (SKBR-3) breast cancer cell lines. METHODS: Cells were treated with varying concentrations of Ukrain for up to 72 h and analyzed for viability by trypan blue exclusion, apoptosis by intracellular caspase 3 and Annexin V staining, and proliferative potential by a clonogenic assay. Female BALB/c mice were challenged subcutaneously (s.c.) with 4T07-RG cells and administered 5 mg/kg or 12.5 mg/kg body weight Ukrain intravenously (i.v.) on the same day and 3 days later. Protective immune responses were determined following re-challenge of tumor-free mice 35 days post primary challenge. RESULTS: Ukrain exposure induced apoptosis in a dose and time-dependent manner with 50 µg/mL Ukrain leading to >50% cell death after 48 h exposure for all three breast cancer cell lines. Ukrain administration (12.5 mg/kg) led to significant inhibition of 4T07 tumor growth in vivo and sustained protective anti-tumor immunity following secondary challenge. CONCLUSION: Our findings demonstrate the in vitro and in vivo cytotoxic effects of Ukrain on breast cancer cells and may provide insight into designing Ukrain-based therapies for breast cancer patients.

British Association for Sexual Health and HIV: framework for guideline development and assessment.

This article has been prepared by the Clinical Effectiveness Group (CEG) of the British Association for Sexual Health and HIV (BASHH) to specify the methodology BASHH requires for guideline development and the process of guideline evaluation by the CEG. This replaces the specifications for the development of UK guidelines on the management of sexually transmitted infections and closely related conditions previously published in this journal in 2004 and updated in 2005.

National audit of asymptomatic screening in UK genitourinary medicine clinics: case-notes audit.

A national audit of screening of asymptomatic patients seen in UK genitourinary medicine clinics in 2009 was conducted against the national guidelines. Data were aggregated by regions and clinics in regions, allowing practice to be compared within and between regions, as well as to national averages and against national guidelines. The case-notes of 4428 patients were audited. Performance was over 80% against the national guidelines for screening of asymptomatic heterosexual men, men who have sex with men (MSM) and women for chlamydial, gonorrhoeal, syphilis and HIV infections. However, the recommended method of endocervical culture for gonorrhoea was performed in only 65% of women, with a further one-quarter being screened with endocervical or vulvovaginal nucleic acid amplification tests (NAATs). Although significant NAAT use for gonorrhoea was seen in all groups, testing for gonorrhoea by culture is still recommended as a first-line test on invasive samples. Over 80% of MSM, who were not known to be immune, were screened for hepatitis B. Urethral microscopy was performed in 22% of heterosexual men and 17% of MSM, and cervical microscopy in 12% of women.

National audit of asymptomatic screening in UK genitourinary medicine clinics: clinic policies audit.

Of clinics responding to the audit, 99 and 97% have policies that are compliant with the British Association for Sexual Health and HIV National Guidelines for testing of asymptomatic men and women for HIV and syphilis, respectively. All clinics offer men, and all but one clinic offer women, screening for chlamydial infection with nucleic acid amplification tests (NAATs), as recommended by the guidelines. However, for gonorrhoea screening one-third of clinics offer men urine or urethral NAATs, and one quarter of clinics offer women endocervical, vulvovaginal or urinary NAATs, and not endocervical culture, and these practices are not compliant with the guidelines. Eight clinics did not specify whether they routinely offer testing for gonorrhoea in women. One-third of clinics routinely perform rectal and oropharyngeal screening for gonorrhoea in men who have sex with men (MSM), but fewer screen for chlamydia, regardless of sexual history which is stated as a determinant of offering screening at these anatomical sites. Finally, one-fifth of clinics offer urethral microscopy to asymptomatic heterosexual men and MSM, and about one half of clinics offer urethral culture for detection of gonorrhoea in asymptomatic women, even though these practices are not compliant with the guidelines.

Effect of capping protein on a growing filopodium.

Filopodia, or the growth of bundles of biological fibers outwards from a biological cell surface while enclosed in a membrane tube, are implicated in many processes vital to life. This study models the effect of capping protein on such filopodia, paying close attention to the polymerization dynamics of biological fiber bundles within long membrane tubes. Due to the effects of capping protein, the number of fibers in the filopodium bundle decreases down the length of the enclosing membrane tube. This decrease in the number of fibers down the length of a growing filopodium is found to have profound implications for the dynamics and stability of filopodia in general. This study theoretically finds that the presence of even a relatively modest amount of capping protein can have a large effect on the growth of typical filopodia, such as can be found in fibroblasts, keratocytes, and neuronal growth cones. As an illustration of this modeling work, this study investigates the striking example of the acrosomal reaction in the sea cucumber Thyone, whose filopodia can grow remarkably quickly to approximately 90 mum in approximately 10 s, and where the number of fibers is known to decrease down the length of the filopodium, presumably due to progressive fiber end-capping occurring as the filopodium grows. Realistic future dynamical theories for filopodium growth are likely to rely on an accurate treatment of the kinds of capping protein effects analyzed in this work.

Convection-enhanced drug delivery of interleukin-4 Pseudomonas exotoxin (PRX321): increased distribution and magnetic resonance monitoring.

Convection-enhanced drug delivery (CED) enables achieving a drug concentration within brain tissue and brain tumors that is orders of magnitude higher than by systemic administration. Previous phase I/II clinical trials using intratumoral convection of interleukin-4 Pseudomonas exotoxin (PRX321) have demonstrated an acceptable safety and toxicity profile with promising signs of therapeutic activity. The present study was designed to assess the distribution efficiency and toxicity of this PRX321 using magnetic resonance imaging (MRI) and to test whether reformulation with increased viscosity could enhance drug distribution. Convection of low- [0.02% human serum albumin (HSA)] and high-viscosity (3% HSA) infusates mixed with gadolinium-diethylenetriamine pentaacetic acid and PRX321 were compared with low- and high-viscosity infusates without the drug, in normal rat brains. MRI was used for assessment of drug distribution and detection of early and late toxicity. Representative brain samples were subjected to histological examination. Distribution volumes calculated from the magnetic resonance images showed that the average distribution of 0.02% HSA was larger than that of 0.02% HSA with PRX321 by a factor of 1.98 (p < 0.02). CED of 3.0% HSA, with or without PRX321, tripled the volume of distribution compared with 0.02% HSA with PRX321 (p < 0.015). No drug-related toxicity was detected. These results suggest that the impeded convection of the PRX321 infusate used in previous clinical trials can be reversed by increasing infusate viscosity and lead to tripling of the volume of distribution. This effect was not associated with any detectable toxicity. A similar capability to reverse impeded convection was also demonstrated in a CED model using acetic acid. These results will be implemented in an upcoming phase IIb PRX321 CED trial with a high-viscosity infusate.