Fatty liver disease is an emerging public health problem without effective therapies, and chronic hepatic inflammation is a key pathologic mediator in its progression. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs), which have potent anti-inflammatory effects. Although promoting the effects of EETs elicits anti-inflammatory and protective effects in the cardiovascular system, the contribution of CYP-derived EETs to the regulation of fatty liver disease-associated inflammation and injury is unknown. Using the atherogenic diet model of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), our studies demonstrated that induction of fatty liver disease significantly and preferentially suppresses hepatic CYP epoxygenase expression and activity, and both hepatic and circulating levels of EETs in mice. Furthermore, mice with targeted disruption of Ephx2 (the gene encoding soluble epoxide hydrolase) exhibited restored hepatic and circulating EET levels and a significantly attenuated induction of hepatic inflammation and injury. Collectively, these data suggest that suppression of hepatic CYP-mediated EET biosynthesis is an important pathological consequence of fatty liver disease-associated inflammation, and that the CYP epoxygenase pathway is a central regulator of the hepatic inflammatory response in NAFLD/NASH. Future studies investigating the utility of therapeutic strategies that promote the effects of CYP-derived EETs in NAFLD/NASH are warranted.
Electrical capacitance, measured between an electrode inserted at the base of a plant and an electrode in the rooting substrate, is often linearly correlated with root mass. Electrical capacitance has often been used as an assay for root mass, and is conventionally interpreted using an electrical model in which roots behave as cylindrical capacitors wired in parallel. Recent experiments in hydroponics show that this interpretation is incorrect and a new model has been proposed. Here, the new model is tested in solid substrates.
The capacitances of compost and soil were determined as a function of water content, and the capacitances of cereal plants growing in sand or potting compost in the glasshouse, or in the field, were measured under contrasting irrigation regimes.
Capacitances of compost and soil increased with increasing water content. At water contents approaching field capacity, compost and soil had capacitances at least an order of magnitude greater than those of plant tissues. For plants growing in solid substrates, wetting the substrate locally around the stem base was both necessary and sufficient to record maximum capacitance, which was correlated with stem cross-sectional area: capacitance of excised stem tissue equalled that of the plant in wet soil. Capacitance measured between two electrodes could be modelled as an electrical circuit in which component capacitors (plant tissue or rooting substrate) are wired in series.
The results were consistent with the new physical interpretation of plant capacitance. Substrate capacitance and plant capacitance combine according to standard physical laws. For plants growing in wet substrate, the capacitance measured is largely determined by the tissue between the surface of the substrate and the electrode attached to the plant. Whilst the measured capacitance can, in some circumstances, be correlated with root mass, it is not a direct assay of root mass.
Barley; Hordeum vulgare; soil capacitance; root mass; electrical circuit; root phenomics; wheat; Triticum aestivum
Isolated hepatic perfusion (IHP) with melphalan is an established approach for patients with unresectable metastatic liver lesions. This study determined the safety and maximum tolerated dose (MTD) of 5-FU with oxaliplatin via IHP.
Standard 3 × 3 Phase I design. Subjects with unresectable isolated CRC liver metastases scheduled for HAI pump were eligible. IHP used fixed-dose oxaliplatin with escalating 5-FU doses. Toxicity (CTCAE v 4.0) and response (RECIST), progression-free survival, and overall survival (OS) were assessed. Systemic and IHP plasma PK of 5-FU, anabolites, and platinum were determined.
All 12 patients had received ≥1 line of pre-IHP chemotherapy. There were 4 grade 3 serious adverse events (33.3 %) and 1 grade 4 event (8.3 %). Also, 2 dose-limiting toxicities occurred at DL2 at 300 mg/m2, resulting in expansion of DL1 at 200 mg/m2 5-FU, the eventual MTD. At 6-month follow-up, 9 patients (82 %) demonstrated partial response, while 2 (18 %) exhibited stable disease. Also, 64 % of patients demonstrated a >50 % decrease in CEA. The 1- and 2-year OS probabilities were 90.9 and 71.6 %, respectively, with median follow-up of 24 months. IHP exposures (AUC0–60 min) were 10.9 ± 4.5 μgPt h/mL, 49.3 ± 30.7 μg h/mL 5-FU (DL1), and 70.5 ± 35.5 μg h/mL 5-FU (DL2). Systemic exposure (AUC0–inf) relative to IHP exposure was negligible for both platinum (1.1 ± 1.5 %) and 5-FU (0.09 ± 0.10 %).
The MTD for IHP was 200 mg/m2 5-FU with 40 mg/m2 oxaliplatin. Systemic exposure to the agents was minimal during IHP. The response and survival observed warrants assessment in a larger phase II trial.
As postsynaptic metabotropic subtype 1 (mGlu1) receptors are present in the thalamus, we have investigated the effect of potentiating and antagonising mGlu1 receptors on responses of thalamic neurones to noxious sensory stimulation. Extracellular recordings were made in vivo with multi-barrel iontophoretic electrodes from single neurones in the thalamus of urethane-anaesthetised rats. Responses to iontophoretic applications of the Group I mGlu agonist 3,5-dihydroxy-phenylglycine (DHPG) were selectively potentiated by co-application of the mGlu1 positive allosteric modulator Ro67-4853, whereas they were selectively reduced upon co-application of the mGlu1 receptor orthosteric antagonist LY367385. This indicates that thalamic DHPG responses are mediated primarily via mGlu1 receptors, consistent with the high postsynaptic levels of this receptor in the thalamus. Furthermore, potentiation of DHPG responses by Ro67-4853 were greater when the initial DHPG response was of a low magnitude. Ro67-4853 also potentiated responses of thalamic neurones to noxious thermal stimulation, whilst having little effect on the baseline activity of nociceptive neurones. By contrast, nociceptive responses were reduced by LY367385. In a further series of experiments we found that inactivation of somatosensory cortex by cooling resulted in a reduction of thalamic nociceptive responses. These results underline the importance of mGlu1 receptors in the processing of sensory information in the thalamus, particularly with respect to nociceptive responses. Furthermore, the involvement of mGlu1 receptors may reflect the activity of descending cortico-thalamic afferents.
•Pharmacological potentiation of mGlu1 receptors enhances nociceptive responses of thalamic neurones.•Antagonism of mGlu1 receptors reduces nociceptive responses of thalamic neurones.•Inactivation of somatosensory cortex reduces nociceptive responses of thalamic neurones.•This suggests a role for mGlu1 receptors and cortico-thalamic pathways in nociceptive processing.
Thalamus; Cortico-thalamic; Metabotropic glutamate receptors; mGlu1; Pain; Nociception
•We investigated the influence of area MT feedback on LGN cell responses to visual stimuli.•We used focal GABA micro-iontophoresis to reversibly block area MT cell responses.•Inactivating area MT feedback produced clear and reversible changes in LGN cell responses.•Effects were observed across magno, parvo and koniocellular LGN cell types.
The feedback connections from the cortical middle temporal (MT) motion area, to layer 6 of the primary visual cortex (V1), have the capacity to drive a cascaded feedback influence from the layer 6 cortico-geniculate cells back to the lateral geniculate nucleus (LGN) relay cells. This introduces the possibility of a re-entrant motion signal affecting the relay of the retinal input through the LGN to the visual cortex. The question is whether the response of LGN cells to moving stimuli involves a component derived from this feedback. By producing a reversible focal pharmacological block of the activity of an MT direction column we show the presence of such an influence from MT on the responses of magno, parvo and koniocellular cells in the macaque LGN. The pattern of effect in the LGN reflects the direction bias of the MT location inactivated. This suggests a moving stimulus is captured by iterative interactions in the circuit formed by visual cortical areas and visual thalamus.
LGN, lateral geniculate nucleus; MT, middle temporal; RF, receptive field; V1, primary visual cortex; lateral geniculate nucleus; feedback influence; area MT
Cerebral blood flow (CBF) increases from rest to ∼60% of peak oxygen uptake (VO2peak) and thereafter decreases towards baseline due to hyperventilation-induced hypocapnia and subsequent cerebral vasoconstriction. It is unknown what happens to CBF in older adults (OA), who experience a decline in CBF at rest coupled with a blunted ventilatory response during VO2peak. In 14 OA (71 ± 10 year) and 21 young controls (YA; 23 ± 4 years), we hypothesized that OA would experience less hyperventilation-induced cerebral vasoconstriction and therefore an attenuated reduction in CBF at VO2peak. Incremental exercise was performed on a cycle ergometer, whilst bilateral middle cerebral artery blood flow velocity (MCA Vmean; transcranial Doppler ultrasound), heart rate (HR; ECG) and end-tidal PCO2 (PETCO2) were monitored continuously. Blood pressure (BP) was monitored intermittently. From rest to 50% of VO2peak, despite greater elevations in BP in OA, the change in MCA Vmean was greater in YA compared to OA (28% vs. 15%, respectively; P < 0.0005). In the YA, at intensities >70% of VO2peak, the hyperventilation-induced declines in both PETCO2 (14 mmHg (YA) vs. 4 mmHg (OA); P < 0.05) and MCA Vmean (−21% (YA) vs. −7% (OA); P < 0.0005) were greater in YA compared to OA. Our findings show (1), from rest-to-mild intensity exercise (50% VO2peak), elevations in CBF are reduced in OA and (2) age-related declines in hyperventilation during maximal exercise result in less hypocapnic-induced cerebral vasoconstriction.
Cerebral blood flow; Humans; Aging; Ventilation; Exercise intensity; Cycling; Life Sciences; Molecular Medicine; Geriatrics/Gerontology; Cell Biology
Laryngeal cancer treatment inherently affects life's most basic functions and significantly affects quality of life (QOL). We aimed to identify which aspects of QOL and which patients are most affected by the various treatment options.
The University of Washington Quality of Life (UW-QOL) questionnaire was administered to all patients with laryngeal cancer treated at a single institution over a seven-year period (2003–2010).
In total, 41 patients responded. All had been treated for squamous cell carcinoma of the larynx. Questionnaires were completed at a median of 18.5 months after treatment. The overall quality of life was 81.1/100 as assessed by the UW-QOL scale, with only 4.9% reporting ‘poor’ or worse QOL. Neither patient age nor time after treatment significantly affected any aspect of QOL. Patients undergoing primary radiotherapy reported the best QOL. Those undergoing chemoradiotherapy or combined surgical treatment and chemoradiotherapy reported the worst QOL, particularly in terms of social eating, taste and saliva production. Patients with a T stage ≥2 and those with nodal metastases reported a significantly worse QOL.
Overall, QOL in our patients was good. This study highlights the aspects of QOL most affected by various treatments for laryngeal cancer and identifies areas in which therapeutic intervention may be focused. It also provides information to guide clinicians when assisting patients to make informed decisions regarding treatment of their head and neck cancer.
University Washington Quality of Life; Head and neck neoplasm
Malignant peripheral nerve sheath tumours are rare and aggressive soft-tissue sarcomas of ectomesenchymal origin. These tumours commonly occur in patients with neurofibromatosis Type 1 with a cumulative lifetime risk of 10%. The vast majority of cases present with clinical evidence of a soft-tissue mass with or without features of nerve irritation and loss of function arising from the lesion of origin. The primary presentation of a malignant peripheral nerve sheath tumour with a pneumothorax in the absence of widespread metastatic disease in a patient with no medical or family history of neurofibromatosis has never been reported in the literature.
We present a unique case of a systemically well 34-year-old male who presented with clinical evidence of a right-sided pneumothorax. The chest radiograph identified the right-sided pneumothorax and revealed an apical pleural mass that was confirmed by intravenous contrast-enhanced CT of the thorax. The patient was referred for video-assisted thorascopic surgical pleurodesis and biopsy of the lesion. Histopathology analyses confirmed the diagnosis of malignant peripheral nerve sheath tumour.
To the best of our knowledge, no such case reports have been published in the literature. A diagnosis of malignant peripheral nerve sheath tumour should be considered as one of the rarer possibilities in patients presenting with pneumothoraces in association with apical pleural lesions.
The incidence, cause, and prognosis of sciatic neuropathy in children is not well understood. We report our 30-year experience of 53 patients with pediatric sciatic neuropathies (SN).
Prospective review of the history, physical examination, electrophysiologic findings, and clinical course of children with SN.
The etiology of SN injury was varied and included trauma (13), iatrogenic causes (13) (8 orthopedic surgeries and 5 miscellaneous surgeries), prolonged extrinsic compression and immobilization (6), tumors (7), vascular (5), idiopathic and progressive (4), infantile and nonprogressive (2), and unknown, presumed postviral (3). Electrophysiologic studies demonstrated abnormalities in motor conduction studies of the peroneal nerve in 44/53 (83%) or tibial nerve in 35/51 (67%). Sensory conduction studies were abnormal in sural nerve in 34 of 43 cases (79%), and superficial peroneal nerves in 15/25 (60%). Needle EMG was abnormal in peroneal innervated muscles in all subjects, in tibial nerve innervated muscles in 43/51 (84%), and in the hamstrings in 18/29 (62%). Prognosis for recovery was variable and depended on the etiology and the severity of the nerve injury.
SN is an uncommon mononeuropathy in children. The causes of SN are varied in children compared to adults. Electrophysiologic studies in children may be limited by poor tolerance but play an important role in establishing the diagnosis.
Metabotropic glutamate subtype 1 (mGlu1) receptor is thought to play a role in synaptic responses in thalamic relay nuclei. The aim of this study was to evaluate the positive allosteric modulator (PAM) Ro67-4853 as a tool to modulate thalamic mGlu1 receptors on single thalamic neurones in vivo. Ro67-4853, applied by iontophoresis onto ventrobasal thalamus neurones of urethane-anaesthetised rats, selectively enhanced responses to the agonist (S)-3,5-dihydroxy-phenylglycine (DHPG), an effect consistent with mGlu1 potentiation. The PAM was also able to enhance maintained responses to 10 Hz trains of sensory stimulation of the vibrissae, but had little effect on responses to single sensory stimuli. Thus Ro67-4853 appears to be a highly selective tool that can be useful in investigating how mGlu1 receptor potentiation can alter neural processing in vivo. Our results show the importance of mGlu1 in sensory processing and attention mechanisms at the thalamic level and suggest that positive modulation of mGlu1 receptors might be a useful mechanism for enhancing cognitive and attentional processes.
► We the studied effects of Ro67-4853, an mGlu1 PAM, on single thalamic cells in vivo. ► Ro67-4853 selectively potentiated responses to the agonist DHPG. ► Ro67-4853 potentiated sensory synaptic responses to repetitive vibrissa stimulation. ► Ro67-4853 is a selective tool to potentiate mGlu1-mediated neural processing in vivo. ► Positive modulation of mGlu1 may be a useful means to enhance cognition and attention.
mGlu1 receptors; Ro67-4853; Thalamus; Cortico-thalamic; Sensory processing; Attention
Pathological gambling (PG) is a form of behavioural addiction that has been associated with elevated impulsivity and also cognitive distortions in the processing of chance, probability and skill. We sought to assess the relationship between the level of cognitive distortions and state and trait measures of impulsivity in treatment-seeking pathological gamblers.
Thirty pathological gamblers attending the National Problem Gambling Clinic, the first National Health Service clinic for gambling problems in the UK, were compared with 30 healthy controls in a case-control design. Cognitive distortions were assessed using the Gambling-Related Cognitions Scale (GRCS). Trait impulsivity was assessed using the UPPS-P, which includes scales of urgency, the tendency to be impulsive in positive or negative mood states. Delay discounting rates were taken as a state measure of impulsive choice.
Pathological gamblers had elevated impulsivity on several UPPS-P subscales but effect sizes were largest (Cohen's d>1.4) for positive and negative urgency. The pathological gamblers also displayed higher levels of gambling distortions, and elevated preference for immediate rewards, compared to controls. Within the pathological gamblers, there was a strong relationship between the preference for immediate rewards and the level of cognitive distortions (R2=0.41).
Impulsive choice in the gamblers was correlated with the level of gambling distortions, and we hypothesize that an impulsive decision-making style may increase the acceptance of erroneous beliefs during gambling play.
Behavioural addiction; decision making; delay discounting; problem gambling; risk taking
Little comparable information is available regarding clinical characteristics of opioid-dependent women from different countries. In the present study, women from the USA, Canada and a Central European country, Austria, screened for participation in the Maternal Opioid Treatment Human Experimental Research study, were compared with respect to their demographic and addiction histories.
Pregnant women (n = 1,074) were screened for study participation using uniformed clinical criteria and instruments. The screening results were compared with regard to exclusion, demographics, drug use, and psychosocial and treatment histories.
Compared to the screened US and Canadian women, Austrian women were more likely to be younger (p < 0.001), white (p < 0.001), had significantly lower levels of educational attainment (p < 0.001), were less likely to use opioids daily (p < 0.001) and more likely to have been prescribed buprenorphine (p < 0.001). Compared to both rural and urban US groups, the Austrian group was less likely to have legal issues (p < 0.001) and was younger when first prescribed agonist medication (p < 0.001).
The differences between North American and European groups may offer unique insights concerning treatment and pregnancy outcomes for opioid-dependent pregnant women.
Pregnancy; Opioid dependence; Methadone; Buprenorphine
HIV sexual-risk and drug-use behavior predictors have been studied in non-pregnant but not pregnant drug-dependent populations.
Examine the ability of the ASI composite scores to predict HIV sexual- and drug-risk scores as well as the individual items of a modified version of the Risk Assessment Battery in drug-using pregnant women.
Pregnant women (N=76) completing pretreatment ASI and HIV-risk questionnaires.
The Legal composite score was the sole significant predictor of the sexual-risk score, with a 1 SD increase in the Legal composite score resulting in a 24% increase in sexual-risk, p<.001. The Medical, Drug, and Legal composite scores were each significant predictors of the drug-risk score, with a 1 SD increase resulting in a 31% decrease, and 121% and 73% increases, respectively, in drug-risk, all ps<.05.
Conclusions and Scientific Significance
Pregnant drug-dependent women and their fetuses are vulnerable to the consequences of both sexual-risk behaviors and drug-use. The ASI may help screen such patients for HIV sexual-risk and drug-use behaviors as a first step in tailoring treatment to address these issues.
substance abuse; pregnancy; sexual behavior; HIV; drug addiction
To test whether more women are screened for sexually transmitted infections when offered home‐based versus clinic‐based testing and to evaluate the feasibility and acceptability of self‐sampling and self‐testing in home and clinic settings in a resource‐poor community.
Women aged 14–25 were randomised to receive a home kit with a pre‐paid addressed envelope for mailing specimens or a clinic appointment, in Gugulethu, South Africa. Self‐collected vaginal swabs were tested for gonorrhoea, chlamydia and trichomoniasis using PCR and self‐tested for trichomoniasis using a rapid dipstick test. All women were interviewed at enrolment on sociodemographic and sexual history, and at the 6‐week follow‐up on feasibility and acceptability.
626 women were enrolled in the study, with 313 in each group; 569 (91%) completed their 6‐week follow‐up visit. Forty‐seven per cent of the women in the home group successfully mailed their packages, and 13% reported performing the rapid test and/or mailing the kit (partial responders), versus 42% of women in the clinic group who kept their appointment. Excluding partial responders, women in the home group were 1.3 (95% CI 1.1 to 1.5) times as likely to respond to the initiative as women in the clinic group. Among the 44% who were tested, 22% tested positive for chlamydia, 10% for trichomoniasis, and 8% for gonorrhoea.
Self‐sampling and self‐testing are feasible and acceptable options in low‐income communities such as Gugulethu. As rapid diagnostic tests become available and laboratory infrastructure improves, these methodologies should be integrated into services, especially services aimed at young women.
non‐cardiac chest pain; hypnotherapy
The paternal origins of Thoroughbred racehorses trace back to a handful of Middle Eastern stallions, imported to the British Isles during the seventeenth century. Yet, few details of the foundation mares were recorded, in many cases not even their names (several different maternal lineages trace back to ‘A Royal Mare’). This has fuelled intense speculation over their origins. We examined mitochondrial DNA from 1929 horses to determine the origin of Thoroughbred foundation mares. There is no evidence to support exclusive Arab maternal origins as some historical records have suggested, or a significant importation of Oriental mares (the term used in historic records to refer to Middle East and western Asian breeds including Arab, Akhal-Teke, Barb and Caspian). Instead, we show that Thoroughbred foundation mares had a cosmopolitan European heritage with a far greater contribution from British and Irish Native mares than previously recognized.
Thoroughbred horse; foundation of breed; maternal origins; phylogenetics; mitochondrial DNA
Little is known about the prevalence and severity of smoking in pregnant opioid dependent patients.
To first characterize the prevalence and severity of smoking in pregnant patients screened for a randomized controlled trial, MOTHER (Maternal Opioid Treatment: Human Experimental Research), comparing two agonist medications; and second, to compare the MOTHER screening sample to published samples of other pregnant and/or substance use disordered patients.
Pregnant women (N=108) screened for entry into an agonist medication comparison study were retrospectively compared on smoking variables to samples of pregnant methadone-maintained patients (N=50), pregnant opioid or cocaine dependent patients (N =240), non-pregnant methadone-maintained women (N =75), and pregnant non-drug-addicted patients (N=1,516).
Of screened patients, 88% (n = 95) smoked for a mean of 140 months (SD=79.0) starting at a mean age of 14 (SD=3.5). This rate was similar to substance use disordered patients and significantly higher compared to general pregnant patients (88% v. 22%, p < .001).
Conclusion and Scientific Significance
Aggressive efforts are needed to reduce/eliminate smoking in substance-abusing pregnant women.
pregnancy; substance abuse; pharmacologic treatment; opioid dependence; methadone; buprenorphine
We determined the prevalence, distribution and correlates of human papillomavirus (HPV) types in 386 mixed-income, sexually active women in São Paulo, Brazil. Endocervical samples were tested for HPV DNA with L1 primers MY09 and MY11; negative and indeterminate samples were retested using GP 5+/6+ consensus primers. HPV was detected in 35% of all women; high-risk/probable high-risk types in 20%; low-risk types in 7%; and an indeterminate type in 10%. Twenty-five HPV types were found overall: 17 (probable) high-risk types and eight low-risk types. Approximately one-third (29%) of women with HPV infection were positive for type 16 or 18 and 36% were positive for types 6, 11, 16 or 18. The presence of (probable) high-risk HPV was associated with younger age, more lifetime sex partners and abnormal vaginal flora. Additional studies mapping the distribution of HPV types worldwide are necessary to prepare for vaccination programmes and direct future vaccine development.
Brazil; human papillomavirus; HPV type; sexually transmitted infections
An efficient Agrobacterium-mediated durum wheat transformation system has been developed for the production of 121 independent transgenic lines. This improved system used Agrobacterium strain AGL1 containing the superbinary pGreen/pSoup vector system and durum wheat cv Stewart as the recipient plant. Acetosyringone at 400 μM was added to both the inoculation and cultivation medium, and picloram at 10 mg l−1 and 2 mg l−1 was used in the cultivation and induction medium, respectively. Compared with 200 μM in the inoculation and cultivation media, the increased acetosyringone concentration led to significantly higher GUS (β-glucuronidase) transient expression and T-DNA delivery efficiency. However, no evident effects of acetosyringone concentration on regeneration frequency were observed. The higher acetosyringone concentration led to an improvement in average final transformation efficiency from 4.7% to 6.3%. Furthermore, the concentration of picloram in the co-cultivation medium had significant effects on callus induction and regeneration. Compared with 2 mg l−1 picloram in the co-cultivation medium, increasing the concentration to 10 mg l−1 picloram resulted in improved final transformation frequency from 2.8% to 6.3%, with the highest frequency of 12.3% reached in one particular experiment, although statistical analysis showed that this difference in final transformation efficiency had a low level of significance. Stable integration of foreign genes, their expression, and inheritance were confirmed by Southern blot analyses, GUS assay, and genetic analysis. Analysis of T1 progeny showed that, of the 31 transgenic lines randomly selected, nearly one-third had a segregation ratio of 3:1, while the remainder had ratios typical of two or three independently segregating loci.
Acetosyringone; Agrobacterium tumefaciens; durum wheat cv Stewart; picloram; transformation
controlled ovarian hyperstimulation; cryopreservation; IVF; oocyte utilization; reproductive efficiency