Bug off! Severe toxicity following inhalational exposure to N, N-diethyl-meta-toluamide (DEET).

N, N-diethyl-meta-toluamide (DEET) is an insect repellent currently used by millions of people since 1956. DEET has an excellent safety profile and has remarkable protection against mosquitoes, ticks and various other arthropods. Toxicity is unusual, and is generally associated with incorrect, or overuse of the product. We report a patient with severe toxicity following inhalational exposure to a "bug bomb". containing 98% DEET.

l-phenylalanine modulates gut hormone release and glucose tolerance, and suppresses food intake through the calcium-sensing receptor in rodents.

OBJECTIVE: High-protein diets (HPDs) are associated with greater satiety and weight loss than diets rich in other macronutrients. The exact mechanisms by which HPDs exert their effects are unclear. However, evidence suggests that the sensing of amino acids produced as a result of protein digestion may have a role in appetite regulation and satiety. We investigated the effects of l-phenylalanine (L-Phe) on food intake and glucose homeostasis in rodents. METHODS: We investigated the effects of the aromatic amino-acid and calcium-sensing receptor (CaSR) agonist l-phenylalanine (L-Phe) on food intake and the release of the gastrointestinal (GI) hormones peptide YY (PYY), glucagon-like peptide-1 (GLP-1) and ghrelin in rodents, and the role of the CaSR in mediating these effects in vitro and in vivo. We also examined the effect of oral l-Phe administration on glucose tolerance in rats. RESULTS: Oral administration of l-Phe acutely reduced food intake in rats and mice, and chronically reduced food intake and body weight in diet-induced obese mice. Ileal l-Phe also reduced food intake in rats. l-Phe stimulated GLP-1 and PYY release, and reduced plasma ghrelin, and also stimulated insulin release and improved glucose tolerance in rats. Pharmacological blockade of the CaSR attenuated the anorectic effect of intra-ileal l-Phe in rats, and l-Phe-induced GLP-1 release from STC-1 and primary L cells was attenuated by CaSR blockade. CONCLUSIONS: l-Phe reduced food intake, stimulated GLP-1 and PYY release, and reduced plasma ghrelin in rodents. Our data provide evidence that the anorectic effects of l-Phe are mediated via the CaSR, and suggest that l-Phe and the CaSR system in the GI tract may have therapeutic utility in the treatment of obesity and diabetes. Further work is required to determine the physiological role of the CaSR in protein sensing in the gut, and the role of this system in humans.

Standardization of definitions in focal therapy of prostate cancer: report from a Delphi consensus project.

PURPOSE: To reach standardized terminology in focal therapy (FT) for prostate cancer (PCa). METHODS: A four-stage modified Delphi consensus project was undertaken among a panel of international experts in the field of FT for PCa. Data on terminology in FT was collected from the panel by three rounds of online questionnaires. During a face-to-face meeting on June 21, 2015, attended by 38 experts, all data from the online rounds were reviewed and recommendations for definitions were formulated. RESULTS: Consensus was attained on 23 of 27 topics; Targeted FT was defined as a lesion-based treatment strategy, treating all identified significant cancer foci; FT was generically defined as an anatomy-based (zonal) treatment strategy. Treatment failure due to the ablative energy inadequately destroying treated tissue is defined as ablation failure. In targeting failure the energy is not adequately applied to the tumor spatially and selection failure occurs when a patient was wrongfully selected for FT. No definition of biochemical recurrence can be recommended based on the current data. Important definitions for outcome measures are potency (minimum IIEF-5 score of 21), incontinence (new need for pads or leakage) and deterioration in urinary function (increase in IPSS >5 points). No agreement on the best quality of life tool was established, but UCLA-EPIC and EORTC-QLQ-30 were most commonly supported by the experts. A complete overview of statements is presented in the text. CONCLUSION: Focal therapy is an emerging field of PCa therapeutics. Standardization of definitions helps to create comparable research results and facilitate clear communication in clinical practice.

L-arginine promotes gut hormone release and reduces food intake in rodents.

AIMS: To investigate the anorectic effect of L-arginine (L-Arg) in rodents. METHODS: We investigated the effects of L-Arg on food intake, and the role of the anorectic gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), the G-protein-coupled receptor family C group 6 member A (GPRC6A) and the vagus nerve in mediating these effects in rodents. RESULTS: Oral gavage of L-Arg reduced food intake in rodents, and chronically reduced cumulative food intake in diet-induced obese mice. Lack of the GPRC6A in mice and subdiaphragmatic vagal deafferentation in rats did not influence these anorectic effects. L-Arg stimulated GLP-1 and PYY release in vitro and in vivo. Pharmacological blockade of GLP-1 and PYY receptors did not influence the anorectic effect of L-Arg. L-Arg-mediated PYY release modulated net ion transport across the gut mucosa. Intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration of L-Arg suppressed food intake in rats. CONCLUSIONS: L-Arg reduced food intake and stimulated gut hormone release in rodents. The anorectic effect of L-Arg is unlikely to be mediated by GLP-1 and PYY, does not require GPRC6A signalling and is not mediated via the vagus. I.c.v. and i.p. administration of L-Arg suppressed food intake in rats, suggesting that L-Arg may act on the brain to influence food intake. Further work is required to determine the mechanisms by which L-Arg suppresses food intake and its utility in the treatment of obesity.

BET 2: Usefulness of IV lidocaine in the treatment of renal colic.

A shortcut review was carried out to establish whether intravenous lidocaine is effective in the management of renal colic. Two studies were directly relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these studies are tabulated. The clinical bottom line is that intravenous lidocaine may be of some benefit in renal colic. However, there are other maybe more effective drugs available.

RETRACTED: The Virtual Cutting Edge: Adolescent Self-injury and YouTube.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief and Authors. We wish to retract the abstract "The Virtual Cutting Edge: Adolescent Self-injury and YouTube," published in the October 2015 issue of Annals. The abstract excessively borrowed from the text and methodology of a previous study published elsewhere.1 All authors recognize the seriousness of this issue and apologize to the editors and readers of Annals. Jeffrey S. Jones, MD Chad Garthe, MD Lindsey Ouellette, MS Jason Seamon, DO Department of Emergency Medicine MSU College of Human Medicine Grand Rapids, MI 1. Lewis SP, Heath NL, St. Denis JM, et al. The scope of nonsuicidal self-injury on YouTube. Pediatrics. 2011;1127:e552-e557.

BET 1: ultrasound for the diagnosis and drainage of suspected peritonsillar abscess.

A shortcut review was carried out to establish whether intraoral ultrasound increased the accuracy of diagnosis and the success of aspiration in adults with suspected peritonsillar abscess (quinsy). Using the reported searches, one paper presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of this best paper are tabulated. It is concluded that emergency physician-performed intraoral ultrasound can reliably diagnose peritonsillar abscess and leads to greater success at aspiration when compared with the traditional landmark technique.

Accidental Chlorine Gas Exposure in a Pediatric Patient: A Case Report.

INTRODUCTION: Chlorine gas is a known irritant of the respiratory tract, which may cause damage to various systems depending on time of exposure and concentration of the gas. Current treatments are mainly supportive. While no definitive studies have been completed to date, it has been noted that treatment with a sodium bicarbonate solution via nebulizer may lead to improved outcomes for patients dealing with chlorine gas exposure. CASE REPORT: We present a case of a nine-year-old child arriving at the emergency department after exposure to chlorine gas. Complete recovery from his symptoms occurred rapidly with the administration of nebulized sodium bicarbonate. DISCUSSION: Inhaled chlorine gas acts as a mucous membrane irritant, with symptoms usually beginning within minutes of exposure. Inhaled nebulized sodium bicarbonate has been suggested as a therapy for chlorine exposure. Although its mechanism of action is not well understood, it is thought that inhaled sodium bicarbonate neutralizes the hydrochloric acid formed when the chlorine gas reacts with the water in the lungs. CONCLUSION: Nebulized sodium bicarbonate solution at a low concentration appeared to rapidly and effectively reverse the symptoms due to chlorine gas inhalation in a young child.

Kisspeptin stimulation of insulin secretion: mechanisms of action in mouse islets and rats.

AIMS/HYPOTHESIS: Kisspeptin is a novel peptide identified as an endogenous ligand of the G-protein-coupled receptor 54 (GPR-54), which plays a crucial role in puberty and reproductive function. High levels of GPR-54 and kisspeptin have been reported in the pancreas and we have previously shown that kisspeptin potentiates glucose-induced insulin release from isolated islets, although the mechanisms underlying this effect were unclear. METHODS: Insulin secretion from isolated mouse islets was measured to characterise the effects of kisspeptin. The effects of kisspeptin on both p42/44 mitogen-activated protein kinase (MAPK) phosphorylation and intracellular Ca(2+)([Ca(2+)](i)) in mouse islets were also investigated. Furthermore, kisspeptin was administered to rats in vivo and effects on plasma insulin levels measured. RESULTS: In the current study, kisspeptin induced a concentration-dependent potentiation of glucose-induced (20 mmol/l) insulin secretion from mouse islets, with maximal effects at 1 micromol/l, but had no effect on insulin secretion at a substimulatory concentration of glucose (2 mmol/l). Activation of GPR-54 by kisspeptin also caused reversible increases in [Ca(2+)](i) in Fura-2 loaded dispersed islet cells. The kisspeptin-induced potentiation of glucose-induced insulin secretion was completely abolished by inhibitors of phospholipase C and p42/44 MAPK, but not by inhibitors of protein kinase C or p38 MAPK. Intravenous administration of kisspeptin into conscious, unrestrained rats caused an increase in circulating insulin levels, whilst central administration of kisspeptin had no effect, indicating a peripheral site of action. CONCLUSIONS/INTERPRETATION: These observations suggest that neither typical protein kinase C isoforms nor p38 MAPK are involved in the potentiation of glucose-induced insulin release by kisspeptin, but intracellular signalling pathways involving phospholipase C, p42/44 MAPK and increased [Ca(2+)](i) are required for the stimulatory effects on insulin secretion. The observation that kisspeptin is also capable of stimulating insulin release in vivo supports the conclusion that kisspeptin is a regulator of beta cell function.

A role for the medial preoptic area in CGRP-induced suppression of pulsatile LH secretion in the female rat.

Calcitonin gene-related peptide (CGRP) is involved in a variety of stress responses and plays a pivotal role in stress-induced suppression of the GnRH pulse generator in the rat. Intracerebroventricular administration of CGRP suppresses luteinizing hormone (LH) pulses and increases Fos expression within the medial preoptic area (mPOA) and paraventricular nucleus (PVN). The aims of the present study were to investigate whether the mPOA or PVN are sites of action for CGRP-induced suppression of LH pulses and whether lipopolysaccharide (LPS), restraint or insulin-induced hypoglycaemia, stressors known to suppress LH pulses, affect mRNA expression for CGRP and its receptor subunits (calcitonin receptor-like receptor (CL) and RAMP-1) in the mPOA and PVN. Micro-infusion of CGRP (50, 250 or 500 pmol) into the mPOA, but not the PVN, dose-dependently suppressed LH pulse frequency. LPS, restraint and hypoglycaemia suppressed RAMP-1 mRNA, but not CL or CGRP mRNA expression in the mPOA. In the PVN, all three stressors suppressed CL mRNA expression, but only LPS or restraint suppressed RAMP-1 mRNA, and CGRP mRNA was unaffected. These results provide evidence that, unlike the PVN, the mPOA might play an important role in the inhibitory effect of CGRP on pulsatile LH secretion. Additionally, CGRP receptor function may be involved in this brain region in stress-induced suppression of the GnRH pulse generator.

Ecological genetics and natural selection in molluscs.

Polymorphic snails of the genus Cepaea have been widely used for research in ecological genetics. Natural selection by selective predation is important in controlling morph frequencies in some populations of C. nemoralis in England. The importance of environmental selection in affecting other patterns of local genetic differentiation of population structure (area effects) is a matter of controversy. Some authors emphasize divergent evolution of whole gene pools between area effects, while others feel that climatic selection acting on individual loci is important. Analysis of 500,000 C. nemoralis snails from throughout Europe shows that there is a strong positive association between gene frequencies at the shell color locus and mean summer temperature, but that no climatic correlations are obvious at other loci. Another species, C. vindobonensis, which has a much simpler system of polymorphism than does C. nemoralis, was investigated in Yugoslavia, in a region where there is known to be intense microclimatic differentiation because of the accumulation of cold air in frost hollows. There was a striking tendency for snails with lightly pigmented shell bands to be found in places with a warm microclimate. Physiological and behavioral experiments demonstrate that this is due primarily to differential energy absorption from sunshine by the different shell phenotypes. As in C. nemoralis, other C. vindobonensis phenotypes show no detectable association with the environment. It is possible that genes whose frequencies cannot be related to environmental selection may have evolved strong linkage interactions with other genes in the population's gene pool. Selection by the ecological environment and the genetic environment may therefore both be important in controlling the genetic structure of snail populations.

The role of corticotrophin-releasing hormone receptors in the calcitonin gene-related peptide-induced suppression of pulsatile luteinising hormone secretion in the female rat.

Corticotrophin-releasing hormone (CRH) plays a pivotal role in the suppression of the gonadotrophin-releasing hormone (GRH) pulse generator in response to stress and intracerebroventricular (i.c.v.) administration of calcitonin gene-related peptide (CGRP). We have previously shown both CRH receptor subtypes, CRH-R1 and CRH-R2, are involved in the stress-induced suppression of LH pulses. The aims of the present study were to examine the role of CRH-R1 and CRH-R2 in CGRP-induced suppression of LH pulses, and to investigate the effects of CGRP on CRH expression in the paraventricular nucleus (PVN) and central nucleus of the amygdala (CeA), which have prominent CRH neurone populations that receive dense CGRP innervations. The suppression of LH pulses by CGRP (1.5 microg i.c.v.) was completely prevented by intravenous administration of the CRH-R1 antagonist SSR125543Q (7.5 mg/rat i.v., 30 min before CGRP), but was not affected by the CRH-R2 antagonist, astressin(2)-B (100 microg i.c.v., 10 min before CGRP). CGRP increased the CRH mRNA expression in PVN and CeA. These results provide evidence of a role for CRH-R1 in mediating the suppressive effects of CGRP on pulsatile LH secretion in the female rat, and additionally raise the possibility of an involvement of PVN and CeA CRH neuronal populations in this suppression.

Neonatal lipopolysaccharide exposure exacerbates stress-induced suppression of luteinizing hormone pulse frequency in adulthood.

Early life exposure to immunological challenge has programming effects on the adult hypothalamo-pituitary-adrenocortical axis stress responsivity, and stress is known to suppress GnRH pulse generator activity, especially LH pulses. We investigated the effects of neonatal exposure to endotoxin on stress-induced suppression of pulsatile LH secretion and the involvement of corticotropin-releasing factor (CRF) receptor mechanisms in adult rats. Pups at 3 and 5 d of age were administered lipopolysaccharide (LPS, 50 microg/kg, ip). At 12 wk of age, they were ovariectomized and implanted with sc 17beta-estradiol capsules and i.v. cannulas. Blood samples (25 microl) were collected every 5 min for 5 h for LH measurement. After 2 h of sampling, rats were given LPS (25 microg/kg, iv). CRF and CRF-R1 and CRF-R2 receptor mRNA was determined by RT-PCR in medial preoptic area (mPOA) micropunches collected at 3 h after LPS administration. There was no difference in basal LH pulse frequency between neonatal LPS- and neonatal saline-treated controls. However, neonatal endotoxin-treated rats exhibited a significantly greater LPS stress-induced suppression of LH pulse frequency. Basal mPOA CRF-R1 expression was unchanged in neonatal LPS- and neonatal saline-treated rats. However, CRF-R1 expression was significantly increased in response to LPS stress in neonatal LPS-treated animals but not in neonatal saline-treated controls. CRF and CRF-R2 expression was unchanged in all treatment groups. These data demonstrate that exposure to bacterial endotoxin in early neonatal life programs long-term sensitization of the GnRH pulse generator to the inhibitory influence of stress in adulthood, an effect that might involve up-regulation of CRF-R1 expression in the mPOA.

Patient selection for prostate focal therapy in the era of active surveillance: an International Delphi Consensus Project.

BACKGROUND: Whole-gland extirpation or irradiation is considered the gold standard for curative oncological treatment for localized prostate cancer, but is often associated with sexual and urinary impairment that adversely affects quality of life. This has led to increased interest in developing therapies with effective cancer control but less morbidity. We aimed to provide details of physician consensus on patient selection for prostate focal therapy (FT) in the era of contemporary prostate cancer management. METHODS: We undertook a four-stage Delphi consensus project among a panel of 47 international experts in prostate FT. Data on three main domains (role of biopsy/imaging, disease and patient factors) were collected in three iterative rounds of online questionnaires and feedback. Consensus was defined as agreement in ⩾80% of physicians. Finally, an in-person meeting was attended by a core group of 16 experts to review the data and formulate the consensus statement. RESULTS: Consensus was obtained in 16 of 18 subdomains. Multiparametric magnetic resonance imaging (mpMRI) is a standard imaging tool for patient selection for FT. In the presence of an mpMRI-suspicious lesion, histological confirmation is necessary prior to FT. In addition, systematic biopsy remains necessary to assess mpMRI-negative areas. However, adequate criteria for systematic biopsy remains indeterminate. FT can be recommended in D'Amico low-/intermediate-risk cancer including Gleason 4+3. Gleason 3+4 cancer, where localized, discrete and of favorable size represents the ideal case for FT. Tumor foci <1.5 ml on mpMRI or <20% of the prostate are suitable for FT, or up to 3 ml or 25% if localized to one hemi-gland. Gleason 3+3 at one core 1mm is acceptable in the untreated area. Preservation of sexual function is an important goal, but lack of erectile function should not exclude a patient from FT. CONCLUSIONS: This consensus provides a contemporary insight into expert opinion of patient selection for FT of clinically localized prostate cancer.

Differential role of corticotrophin-releasing factor receptor types 1 and 2 in stress-induced suppression of pulsatile luteinising hormone secretion in the female rat.

Corticotrophin-releasing factor (CRF) plays a pivotal role in stress-induced suppression of the gonadotrophin-releasing hormone pulse generator. We have previously shown that type 2 CRF receptors (CRF(2)) mediate restraint stress-induced suppression of luteinising hormone (LH) pulses in the rat. The present study aimed: (i) to determine whether type 1 CRF receptors (CRF(1)) are also involved in this response to restraint and (ii) to investigate the differential involvement of CRF(1) and CRF(2) in the suppression of LH pulses in response to the metabolic perturbation of insulin-induced hypoglycemia and the innate immunological challenge of lipopolysaccharide (LPS). Ovariectomised rats with oestrogen replacement were implanted with intracerebroventricular (i.c.v.) and intravenous (i.v.) cannulae. Blood samples (25 microl) were collected every 5 min for 5 h for LH measurement. After 2 h of controlled blood sampling, rats were either exposed to restraint (1 h) or injected intravenously with insulin (0.25 IU/kg) or LPS (5 microg/kg). All three stressors suppressed LH pulses. The CRF(1) antagonist SSR125543Q (11.5 micromol/rat i.v., 30 min before stressor) blocked the inhibitory response to restraint, but not hypoglycaemia or LPS stress. In addition to its effect on restraint, the CRF(2) antagonist astressin(2)-B (28 nmol/rat i.c.v., 10 min before insulin or LPS) blocked hypoglycaemia or LPS stress-induced suppression of LH pulses. These results suggest that hypoglycaemia and LPS stress-induced LH suppression involves activation of CRF(2) while restraint stress-induced inhibition of LH pulses involves both CRF(1) and CRF(2).

Dysregulation of the insulin/IGF binding protein-1 axis in transgenic mice is associated with hyperinsulinemia and glucose intolerance.

The insulin/IGF binding protein-1 (IGFBP-1) axis is important in coordinating insulin- and IGF-mediated regulation of glucose metabolism and glycemia. Dysregulation of the axis may play a role in the pathophysiology of disorders of insulin deficiency and resistance. We have investigated this hypothesis by generating transgenic mice that overexpress hIGFBP-1. To study the axis in its true physiological context, we used a human (h) IGFBP-1 cosmid clone so that transgene expression is responsive to normal hormonal stimuli. hIGFBP-1 mRNA is expressed in a tissue-specific fashion, and measurement of serum protein levels by specific immunoassay indicates normal physiological regulation in response to fasting/feeding and appropriate post-translational modification as indicated by the detection of phosphorylated and nonphosphorylated isoforms of the protein. The hypoglycemic response to exogenous IGF-I is attenuated in transgenic mice. Transgenic mice exhibit an enhanced insulin secretory response to a glucose challenge, although basal and stimulated blood glucose levels are similar to controls. There is a sexual dimorphism in phenotypic expression: male transgenic mice had higher stimulated glucose and insulin levels than did females. Transgenic mice exhibit fasting hyperglycemia and hyperinsulinemia and glucose intolerance in later life, indicating an age-related decline in glucocompetence. These findings demonstrate the importance of the normal inverse relationship between serum insulin and IGFBP-1 levels in glucoregulation and that sustained dysregulation of the insulin/IGF-I/IGFBP-1 axis is associated with impaired glucose tolerance and abnormalities of insulin action.