Local cooling during hot water immersion improves perceptions without inhibiting the acute interleukin-6 response.

PURPOSE: Passive elevation of body temperature can induce an acute inflammatory response that has been proposed to be beneficial; however, it can be perceived as uncomfortable. Here, we investigate whether local cooling of the upper body during hot water immersion can improve perception without inhibiting the interleukin-6 (IL-6) response. METHODS: Nine healthy male participants (age: 22 ± 1 years, body mass: 83.4 ± 9.4 kg) were immersed up to the waist for three 60-min water immersion conditions: 42 °C hot water immersion (HWI), 42 °C HWI with simultaneous upper-body cooling using a fan (FAN), and 36 °C thermoneutral water immersion (CON). Blood samples to determine IL-6 plasma concentration were collected pre- and post-water immersion; basic affect and thermal comfort were assessed throughout the intervention. RESULTS: Plasma IL-6 concentration was higher for HWI and FAN when compared with CON (P < 0.01) and did not differ between HWI and FAN (P = 0.22; pre to post, HWI: 1.0 ± 0.6 to 1.5 ± 0.7 pg·ml-1, FAN: 0.7 ± 0.5 to 1.1 ± 0.5 pg·ml-1, CON: 0.5 ± 0.2 to 0.5 ± 0.2 pg·ml-1). At the end of immersion, basic affect was lowest for HWI (HWI: - 1.8 ± 2.0, FAN: 0.2 ± 1.6, CON 1.0 ± 2.1, P < 0.02); thermal comfort for HWI was in the uncomfortable range (3.0 ± 1.0, P < 0.01 when compared with FAN and CON), whereas FAN (0.7 ± 0.7) and CON (-0.2 ± 0.7) were in the comfortable range. CONCLUSION: Local cooling of the upper body during hot water immersion improves basic affect and thermal comfort without inhibiting the acute IL-6 response.

Investigating Wilms' Tumours Worldwide: A Report of the OxPLORE Collaboration-A Cross-Sectional Observational Study.

BACKGROUND: Childhood cancer is neglected within global health. Oxford Pediatrics Linking Oncology Research with Electives describes early outcomes following collaboration between low- and high-income paediatric surgery and oncology centres. The aim of this paper is twofold: to describe the development of a medical student-led research collaboration; and to report on the experience of Wilms' tumour (WT). METHODS: This cross-sectional observational study is reported as per STROBE guidelines. Collaborating centres included three tertiary hospitals in Tanzania, Rwanda and the UK. Data were submitted by medical students following retrospective patient note review of 2 years using a standardised data collection tool. Primary outcome was survival (point of discharge/death). RESULTS: There were 104 patients with WT reported across all centres over the study period (Tanzania n = 71, Rwanda n = 26, UK n = 7). Survival was higher in the high-income institution [87% in Tanzania, 92% in Rwanda, 100% in the UK (X2 36.19, p < 0.0001)]. Given the short-term follow-up and retrospective study design, this likely underestimates the true discrepancy. Age at presentation was comparable at the two African sites but lower in the UK (one-way ANOVA, F = 0.2997, p = 0.74). Disease was more advanced in Tanzania at presentation (84% stage III-IV cf. 60% and 57% in Rwanda and UK, respectively, X2 7.57, p = 0.02). All patients had pre-operative chemotherapy, and a majority had nephrectomy. Post-operative morbidity was higher in lower resourced settings (X2 33.72, p < 0.0001). Methodology involving medical students and junior doctors proved time- and cost-effective. This collaboration was a valuable learning experience for students about global research networks. CONCLUSIONS: This study demonstrates novel research methodology involving medical students collaborating across the global south and global north. The comparison of outcomes advocates, on an institutional level, for development in access to services and multidisciplinary treatment of WT.

Exploring the meaning of quality of life for assisted living residents: A photo-elicitation study.

Assisted living is a popular alternative to residential care, promoting independence and enabling self-care through a supportive living environment. Practitioner understanding of quality of life (QoL) experiences are vital to facilitate good physical and mental health in assisted living. An idiographic case study approach explored resident experiences by combining photo-elicitation and interpretive phenomenological analysis. QoL was understood through three themes: facilitation of identity coherence and transition, the essential nature of socialising, and perceptions of a supportive environment. Assisted living has the potential to act as a bearer for cues of identity continuity with nostalgic devices facilitating environment transition and limiting biographical disruption. Furthermore, opportunities for social contact offer a protective function for residents adapting to negative life challenges such as bereavement. To foster health and QoL in withdrawn residents' facilities should develop peer support programmes with benefits for both mentor and mentee.

Major obstetric haemorrhage of 2000 ml or greater: a clinical audit.

Haemorrhage remains a leading cause of maternal death. We conducted an audit to identify strategies to improve the management at our local NHS Trust. A data collection form was based on our local guideline. A coded database search was conducted for all deliveries where the estimated blood loss was ≥2000 ml (from June 1 2015 to December 31 2015), returning 68 search results (13.7/1000 births). Fifty-six records were included. Poor compliance (<75%) was seen in some key areas including the major obstetric haemorrhage (MOH) call activation (52%), the presence of an anaesthetic consultant (63%) and tranexamic acid administration (46%). Thirty out of 56 cases (54%) were acutely transfused. Women, who were not transfused acutely, appeared to be more likely to need a secondary transfusion if no MOH call had been activated (9/27 (33%) versus 3/29 (10%), p = .052). A key area for improvement was the activation of MOH calls. Following this audit, we adjusted our guideline to make it more clinically useful and staff training sessions were held, including simulation training. Impact statement What is already known on this subject? A postpartum haemorrhage (PPH) is an obstetric emergency. A structured approach is important to optimise the care of the mothers during this dangerous time, and has been shown to reduce the transfusion requirements. However, clinical practice may not adhere to the guideline recommendations. What the results of this study add? With the objective evidence of increased rates of PPH ≥2000 ml at our institution, our work identifying the flaws in management was a critical component of the work to improve the outcomes. This study gives impetus to find innovative ways to improve adherence to guidelines, and inspired an update of our local guideline to improve the applicability and utility. This project suggests a new marker for the adequacy of an acute management (a requirement for secondary blood transfusion without having received an acute transfusion), and raises questions about what constitutes optimum PPH management. What the implications are of these findings for clinical practice and/or further research? The primary and secondary transfusion data raised new questions to investigate in the future: does the involvement of consultants and the escalation of care via the instigation of major haemorrhage protocols improve decision-making and patient outcomes? Does the necessity for a secondary transfusion indicate a suboptimal acute care?

Neural basis of orientation perception in primate vision.

Orientational differences in human visual acuity can be related parametrically to the distribution of optimal orientations for the receptive fields of neurons in the striate cortex of the rhesus monkey. Both behavioral measures of acuity and the distribution of receptive fields exhibit maximums for stimuli horizontal or vertical relative to the retina; the effect diminishes with distance from the fovea. The anisotropy in the neuronal population and in visual acuity appear to be determined by postnatal visual experience.

Relative expression of progesterone receptors A and B in endometrioid cancers of the endometrium.

The nuclear receptor for the female hormone progesterone (PR) is widely expressed in uterine cancer. PR is expressed as two proteins (PRA and PRB) with different functions, and in vitro evidence reveals PRA to inhibit PRB function, so the cellular ratio of PRA:PRB is likely to be an important determinant of progesterone action. The relative expression of PRA and B and their involvement in the pathogenesis of endometrial cancer is not known. The aims of this study were to determine PRA and B expression by dual immunofluorescent histochemistry in endometrial adenocarcinomas compared with expression in normal and hyperplastic glands, and to correlate expression in tumors with clinical features including grade. Significantly lower PR levels were found in tumors compared with normal glands and areas of complex atypical hyperplasia within the same specimen. The normal glands expressed both of the isoforms at similar levels, whereas there was increased predominance of one isoform in hyperplastic areas and in tumors, which suggested that the loss of coordinated expression of PR isoforms was an early event in tumor progression. The majority of tumors [27 (58%) of 46] expressed only one PR isoform, and the proportion expressing either PRA or B was the same [14 (30%) of 46, and 13 (28%) of 46, respectively]. One-half of all tumors ([23 (50%) of 46] expressed either PRA only or a predominance of PRA, and a few tumors [10 (22%) of 46] expressed comparable levels of PRA and B. Similar levels of PRA and B were noted only in FIGO grade 1 tumors, whereas higher grades (2 and 3) were associated with a predominance of one isoform. In summary, expression of only one PR isoform was common in endometrial cancers, which indicates that the decreased PR levels observed in these cancers arise from the loss of one PR isoform. Expression of a single PR isoform was associated with higher clinical grade, which suggests a relationship between the loss of PR isoform expression and features of poorer prognosis. Disruption of relative PR isoform expression was observed in complex atypical hyperplasia, which suggests that early alterations in the ratio of PRA:PRB may precede and/or be implicated in the development of endometrial adenocarcinoma. Alterations in the ratio of PR isoform expression are likely to cause disordered regulation of target genes, resulting in altered progestin action in the uterus, and this may be involved in the pathogenesis of endometrial cancer.

Photoaffinity labelling of the beta-methoxyacrylate binding site in bovine heart mitochondrial cytochrome bc1 complex.

A carbene-generating 14C-labelled beta-methoxyacrylate derivative ((E)-methyl-3-methoxy-2-[4-(3-trifluoromethyl-3-diazirinyl) benzoyloxyphenyl] propanoate, uniformly labelled with 14C in the benzene ring of the benzoyl group) has been used to locate the proteins involved in binding this class of inhibitors to bovine heart mitochondrial ubihydroquinone:cytochrome c oxidoreductase. The beta-methoxyacrylate photoaffinity label was shown to be a competent inhibitor of electron transport through the protein complex. Under illumination through a narrow bandpass filter, allowing specific photolysis of the diazirine group, the compound bound to cytochrome b and weakly to an 8 kDa polypeptide. Apart from some binding to a cytochrome b aggregate, other proteins were left unlabelled. The binding could be prevented in the presence of excess amounts of unlabelled beta-methoxyacrylate, myxothiazol or stigmatellin but not by antimycin A or HQNO. At high concentrations DBMIB partially competed for the binding site. The binding site for this class of inhibitors is therefore the 'o-site'. Our results indicate that this site is comprised of residues from cytochrome b and possibly the 8 kDa polypeptide and that the site may be close to the Reiske iron-sulphur protein.

Rapid hematopoietic recovery after multicycle high-dose chemotherapy: enhancement of filgrastim-induced progenitor-cell mobilization by recombinant human stem-cell factor.

PURPOSE: To assess the mobilization potential and safety of recombinant human stem-cell factor (SCF) when coadministered with filgrastim to untreated women with poor-prognosis breast cancer. PATIENTS AND METHODS: Eligible women had breast cancer with 10 or more positive axillary nodes, or estrogen receptor-negative tumor with 4 positive nodes, or stage III disease. Patients were randomized to receive SCF plus filgrastim or filgrastim alone. Filgrastim 12 microg/kg daily was administered for 6 days by continuous subcutaneous infusion. SCF was administered by daily subcutaneous injection at 5, 10, or 15 microg/kg concurrent with filgrastim for 7 days, or 10 microg/kg daily starting 3 days before filgrastim for a total of 10 days (SCF pretreatment). Apheresis was performed on days 5, 6, and 7 of filgrastim administration. Patients then had three cycles of epirubicin 200 mg/m2 and cyclophosphamide 4 g/m2 every 28 days, each supported by one third of the apheresis product. RESULTS: Sixty-two women were treated. Greater yields occurred in patients who received SCF 10 microg/kg daily plus filgastim than those who received filgrastim alone (P=.013 for CD34+ cells; P=.07 for granulocyte-macrophage colony-forming cells [GM-CFCs]). The difference was more marked with SCF-pretreatment than concurrent SCF. Fewer aphereses were required to reach the predetermined target of peripheral-blood progenitor/stem cells (PBPCs) in women who received SCF. SCF was generally well tolerated. Hematologic recovery was rapid after each of the three cycles of chemotherapy. There was no difference in recovery between the different treatment groups. CONCLUSION: Mobilization of PBPCs by filgrastim is significantly enhanced by coadministration of SCF, and commencing SCF before filgrastim can optimize this effect. SCF has the potential to reduce the number of aphereses required to collect a target number of PBPCs.

Granulocyte-macrophage colony-stimulating factor is not responsible for residual thrombopoiesis in mpl null mice.

OBJECTIVE: To examine the role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in thrombopoiesis. MATERIALS AND METHODS: Thrombopoietin-unresponsi ve mice (mpl null mice), which have a profound reduction in platelets and mature megakaryocytes, were interbred with mice that do not respond to GM-CSF or interleukin 5 (betac null mice), and hematopoiesis was examined. In initial experiments on a mixed genetic background, double mutant mice (betac/mpl null mice) showed an unexpected amelioration of the thrombocytopenia seen in mpl null mice. Platelet counts were elevated approximately twofold in betac/mpl null mice compared with mpl null mice (mpl null 73+/-31; betac/mpl null 164+/-70; n = 10 to 29 mice per genotype, p<0.00001). This was associated with lessening of the deficit of megakaryocytes, progenitor cells, and colony-forming units spleen seen in mpl null mice. This amelioration of the mpl null phenotype in betac/mpl null mice on a mixed genetic background was highly statistically significant. To determine whether this amelioration of phenotype was solely the consequence of loss of betac signaling, progeny of a second intercross on a C57BL/6 background (B6betac/mpl null mice) were examined. When the resulting B6betac/mpl null mice were analyzed and compared with B6mpl null littermates, the increase in platelet count, hematopoietic progenitor cell number, and colony-forming units spleen number was no longer observed. CONCLUSION: There was no additional effect seen as a result of loss of betac signaling. GM-CSF did not play a significant role in thrombopoiesis, even in combination with the absence of thrombopoietin signaling. These results highlight problems that can be encountered when studying introduced mutations in mice. They exemplify the importance of eliminating the influence of modifying genes when attributing biologic differences to specific introduced genetic alterations.

Thrombopoietin signaling is required for in vivo expansion of IL-11--responsive hematopoietic progenitor cells in the steady state.

OBJECTIVE: mpl(-/-) mice have a profound defect in platelets and megakaryocytes and a defect in hematopoietic progenitor cells and stem cells. However, no specific subset of the progenitor/stem cell compartment has been shown to be particularly affected by this deficiency in mpl(-/-) mice. In this article, we identified a specific subset of bone marrow progenitor/stem cells that was altered in mpl(-/-) mice. MATERIALS AND METHODS: In vitro and in vivo hematopoietic assays were utilized to examine the response to interleukin-11 in mice lacking the receptor for thrombopoietin (TPO) (mpl(-/-) mice). RESULTS: The interleukin (IL)-11-responsive subset of progenitor cells was not detected in clonal cultures of bone marrow cells from mpl(-/-) mice. However, mpl(-/-) mice responded to IL-11 in vivo as evidenced by a rise in platelet count and an increase in spleen weight. Experiments were performed to address this paradox: administration of 5-fluorouracil with consequent "expansion" of early hematopoietic cells resulted in the appearance of IL-11-responsive cells in mpl(-/-) mice when assayed in in vitro cultures. CONCLUSIONS: Thus, although mpl(-/-) mice have the capacity to produce IL-11-responsive progenitor cells, under steady state conditions their expansion is dependent on TPO. This is the first evidence that a specific subset of bone marrow progenitor/stem cells is altered in mpl(-/-) mice.

Reduction in the response to coronary and iliac artery injury with photodynamic therapy using 5-aminolaevulinic acid.

OBJECTIVE: Photodynamic therapy (PDT) uses red light (non-thermal, non-ionising) to activate a previously administered photosensitizing drug. This inhibits neointimal hyperplasia in injured arteries in small animals where it appears safe and well tolerated. Our aim was to develop a method for percutaneous application of PDT to iliac and coronary arteries in a large animal model and investigate its influence on the remodeling and intimal hyperplastic response to balloon injury. METHODS: Studies were undertaken on 13 juvenile Large White-Landrace crossbred pigs (15-20 kg). After intravenous administration of the photosensitizing agent 5-amino laevulinic acid (ALA), the arterial tree was accessed via the left common carotid artery and balloon injuries made by over-distension in both common iliacs (thirteen animals) and one or two main coronary arteries (eight animals). Half the injured sites were then illuminated with red laser light transmitted via the catheter. Animals were culled 28 days later and tissue harvested for histomorphometry. RESULTS: Compared with control injured vessels, PDT treated, balloon injured coronary arteries had a larger lumen (1.4 vs. 0.8 mm2, P = 0.002), larger area within the external elastic lamina (2.8 vs. 2.2 mm2, P = 0.006) and smaller area of neointimal hyperplasia (0.4 vs. 0.7 mm2, P = 0.06), 28 days after intervention. Less neointimal hyperplasia and the absence of negative remodeling resulted in the lumen of PDT-treated, injured segments being the same as that of adjacent reference segments (1.5 vs. 1.6 mm2). Similar trends, but with smaller differences, were seen in the iliac vessels. CONCLUSIONS: Intra-arterial, trans-catheter PDT favourably influences the arterial response to balloon injury in both the coronary and peripheral circulations. This technique offers a promising new approach to restenosis after endovascular procedures.

Effects of hypothermia on traumatic brain injury in immature rats.

Hypothermia is beneficial in adult models of traumatic brain injury (TBI), but it has not been evaluated in an immature animal model. We hypothesized that brief hypothermia applied after TBI would reduce cerebral edema and lesion volume in immature rats. Male Wistar rats (3-4 weeks of age, 90-140 g) were anesthetized, intubated, mechanically ventilated, and subjected to TBI by weight drop onto the exposed right parietal cortex. Hypothermic rats were then cooled to a brain temperature of 32.0 +/- 0.5 degrees C for 4 h, and control rats were maintained at a brain temperature of 37.0 +/- 0.5 degrees C. Cerebral edema (wet - dry weight method) was assessed at 5 days. At 4 h, a reduction of percent brain water in the traumatized hemisphere was observed in hypothermic versus normothermic rats (81.75 +/- 0.60 vs. 82.53 +/- 0.67%; p<0.05), but by 24 h posttrauma, the groups were similar (p = 0.82). Total lesion volume (47.2 +/- 8.5 vs. 44.4 +/- 10.0 mm3; p = 0.51) and necrotic volume (20.2 +/- 6.3 vs. 20.0 +/- 7.9 mm3; p = 0.95) were similar in the hypothermic and normothermic groups. We conclude that in this model, a transient (4-h) application of moderate (32 degrees C) hypothermia reduces the cerebral edema characteristically seen in immature rats at 4 h, but this reduction is not sustained at 24 h. Attenuating or delaying the development of cerebral edema could have important therapeutic relevance after TBI. Transient hypothermia, however, did not reduce lesion volume at 5 days posttrauma.

Amblyopic contrast sensitivity: insensitivity to unsteady fixation.

Functional amblyopia (a typically unilateral loss of visual acuity of unknown origin) is frequently accompanied by unsteady fixation. Measurements taken under conditions of retinal-image stabilization indicate that this fixation problem does not contribute to the currently measured losses in spatial contrast sensitivity of the amblyopic eye. Indeed, retinal image motions recorded from unsteadily fixating eyes do not produce spatial contrast sensitivity losses when superimposed on the central field of a normal subject, indicating that such losses are not an immediate consequence of unsteady fixation.

Spatial and chromatic properties of neurons subserving foveal and parafoveal vision in rhesus monkey.

The response properties of neurons in the region of striate cortex subserving central retina (0 degrees-2 degrees) and in a region of representation of parafoveal retina (4 degrees-7 degrees) were studied in unanesthetized paralyzed macaque monkeys. Neurons sensitive to the orientation of the stimulus in the visual field (simple, complex, and hypercomplex), and neurons lacking orientation selectivity (concentric, and a new class termed uniform) were found. In foveal cortex non-oriented cells were more numerous, and orientation sensitive cells had less strict spatial stimulus requirements than in parafoveal cortex. Most neurons received a monocular input, either exclusively or very predominantly. Three types of neurons were recognized on the basis of their responses to chromatic stimuli. (1) Luminosity neurons (about half the population) gave the same qualitative response to all effective wayelengths and had a spectral sensitivity similar to that of the macaque, determined behaviorally. Cells with all spatial types of receptive fields, except simple, occurred in this group. (2) Spectrally-treated neurons also responded in the same manner to different wavelengths, but over a narrower range than luminosity neurons, and their maximal sensitivity was shifted toward one or the other end of the visible spectrum. All tuned neurons had uniform or complex receptive field. (3) Spectrally-opponent neurons were either excited or inhibited by long wavelengths and responded in the opposite manner to short wavelengths. For cells with uniform or complex receptive fields the two opponent systems were coextensive. Simple or concentric neurons often had dual-opponent organization. The distribution of functional types among different cortical layers was similar in parafoveal and foveal cortex. The functional attributes of ocular dominance and orientation sensitivity were found to be statistically independent dimensions of cortical organization. On the other hand, the correlation between spatial and chromatic properties did not vary between different cytoarchitectonic layers, a finding suggesting that these neuronal properties depend on conjoined projectional and intracortical connecting mechanisms.

Effect of systemic hyperandrogenism on the adrenal response to adrenocorticotropin hormone.

A virilized patient with an androgen-producing ovarian tumor was used to illustrate the effect of chronic hyperandrogenism on the adrenal response to ACTH. The accumulation rates of substrates for 3 beta-ol dehydrogenase, 21-hydroxylase, and 11 beta-hydroxylase remained unchanged after oophorectomy. This suggests that chronic hyperandrogenism does not affect the activity of enzymes involved in adrenal steroidogenesis.

Head injuries in children and adults.

Motor vehicle-related accidents account for the largest number of head injuries in all ages. This article reviews types of injury, neurologic assessment, secondary injury, brain swelling, seizures, resuscitation, and intensive care.

Application of Azoxystrobin for Control of Benomyl-Resistant Guignardia citricarpa on 'Valencia' Oranges in South Africa.

Azoxystrobin was evaluated in replicated small-plot trials from 1995 to 1999 for control of citrus black spot (CBS) on 'Valencia' oranges caused by Guignardia citricarpa. Applications of different rates of tank mixes of azoxystrobin and mancozeb during the susceptible period from October to January were compared with an untreated control as well as the standard four applications of mancozeb with or without mineral oil (1.20 g a.i./liter + 0.5% [vol/vol]/liter and 1.60 g a.i./liter of water, respectively). Two applications of azoxystrobin in tank mixtures with mancozeb and mineral oil (0.5% [vol/vol]/liter) in mid-November and mid-January at rates of 0.10, 0.15, and 0.20 g a.i./liter controlled CBS by more than 98 to 99%, 99 to 100% and 95 to 98%, respectively. Concomitantly, where mineral oil was not added to the fungicide mixture, azoxystrobin and mancozeb resulted only in 73 to 95%, 74 to 93% and 92.2 to 92.3% CBS control, respectively. Tank mixtures of benomyl, mancozeb, and mineral oil reduced CBS by only 29%, which could be attributed to the presence of benomyl-resistant pathogen isolates in the experimental orchard. Azoxystrobin applied at rates of 0.05, 0.075, and 0.10 g a.i./liter in tank mixtures with mancozeb (1.2 g a.i./liter) and mineral oil (0.5% [vol/vol]/liter of water) or Agral 90 (0.5% [vol/vol]/liter of water) were equally effective, reducing CBS by more than 99%. When mineral oil was compared to different adjuvants in tank mixtures with azoxystrobin and mancozeb, only mineral oil resulted in 100% clean exportable fruit. There was no difference between Sunspray 6E and Bac oil when mixed with azoxystrobin and mancozeb on the degree of disease control. Furthermore, the concentration of mineral oil in water can be lowered from 0.5% (vol/vol)/liter of water to 0.3% (vol/vol)/liter of water without a loss in efficacy against CBS. It is therefore, recommended that azoxystrobin (0.075 g a.i./liter) must be applied in tank mixtures with mancozeb (1.2 g a.i./liter) and mineral oil, which can be applied at either 0.5% (vol/vol)/liter of water or 0.3% (vol/vol)/liter of water.

A response to the interdisciplinary continuing education dilemma.

The paucity of interdisciplinary continuing education activities and the lack of a mechanism for developing collaborative efforts between and among disciplines are important concerns of continuing health educators. Interested parties in Virginia have established an organization, the Virginia Association for Continuing Education in the Health Professions (VACEHP) to address these concerns. The mission of this association is to meet the needs of planners of continuing education in health fields. The purpose of this article is twofold: to provide background information regarding the origin of VACEHP and to relate the methodology and findings of a Delphi study conducted to assess the needs of the association's membership. The findings of the study are being used by VACEHP to chart a course for developing a statewide interdisciplinary network for continuing education in the health professions.

Oleoyl-L-carnitine inhibits glycine transport by GlyT2.

BACKGROUND AND PURPOSE: Concentrations of extracellular glycine in the CNS are regulated by two Na(+)/Cl(-) -dependent glycine transporters, GlyT1 and GlyT2. Selective inhibitors of GlyT1 have been developed for the treatment of schizophrenia, whilst selective inhibitors of GlyT2 are analgesic in animal models of pain. We have assessed a series of endogenous lipids as inhibitors of GlyT1 and GlyT2. EXPERIMENTAL APPROACH: Human GlyT1 and GlyT2 were expressed in Xenopus laevis oocytes, and the inhibitory actions of a series of acylcarnitines on glycine transport were measured using electrophysiological techniques. KEY RESULTS: Oleoyl-L-carnitine inhibited glycine transport by GlyT2, with an IC(50) of 340 nM, which is 15-fold more potent than the previously identified lipid inhibitor N-arachidonyl-glycine. Oleoyl-L-carnitine had a slow onset of inhibition and a slow washout. Using a series of chimeric GlyT1/2 transporters and point mutant transporters, we have identified an isoleucine residue in extracellular loop 4 of GlyT2 that conferred differences in sensitivity to oleoyl-L-carnitine between GlyT2 and GlyT1. CONCLUSIONS AND IMPLICATIONS: Oleoyl-L-carnitine is a potent non-competitive inhibitor of GlyT2. Previously identified GlyT2 inhibitors show potential as analgesics and the identification of oleoyl-L-carnitine as a novel GlyT2 inhibitor may lead to new ways of treating pain.

10p for an angiogram: the cardio-oesophageal reflex.

A 57-year-old man presented at our institution with central chest pain. Serial ECGs showed dynamic T-wave changes, suggesting the possibility of unstable angina. Urgent coronary angiography revealed an unexpected finding of a radio-opaque lesion seen in the xiphisternal region during screening. Oesophogastroduodenoscopy confirmed this to be a 10p coin. The coin passed through the gastrointestinal tract without complications and the patient's symptoms and ECG changes resolved. This unusual case is a reminder that many diseases may electrocardiographically imitate an acute coronary syndrome.