Unusual presentation for small lymphocytic lymphoma: Case report of a man with bilateral ear involvement and review of the literature.

INTRODUCTION: Ear involvement by non-Hodgkin lymphoma is quite rare and can be mistaken for other common lesions encountered in otolaryngology. The literature on this subject is also limited. CASE SUMMARY: A 45-year-old man with bilateral ear nodules that progressed over two years. Biopsy of the right ear revealed a B-cell small lymphocytic lymphoma (SLL). The patient responded to radiotherapy well. He received an additional dose two months after the initial treatment because of a remaining nodularity on the right earlobe. After several months, he presented a new lesion on his nasal tip, for which a biopsy confirmed a lymphoma relapse. The patient was managed with oral prednisone and low-dose radiation with a favourable response. DISCUSSION: This case highlights the importance of including lymphoma in the differential diagnosis of ear lesions from an otolaryngology perspective. A biopsy of any lesion or nodule with an atypical course should be considered for appropriate diagnosis and management.

Differential engagement of polar networks in the glucagon-like peptide 1 receptor by endogenous variants of the glucagon-like peptide 1.

The glucagon-like peptide 1 receptor (GLP-1R) can be activated by a number of endogenous peptide hormones, including extended, processed, glycine extended and carboxy-terminally amidated versions of glucagon-like peptide 1 (GLP-1). While the main focus of the literature has been on the processed, amidated form, GLP-1(7-36)NH2, the other forms of this peptide are likely to be secreted in physiologically relevant amounts under certain circumstances. This study builds on our existing work examining the effect of mutation of conserved transmembrane polar residues within the receptor to understand the nature of binding and pleiotropic signaling in response to these alternatively processed versions of this important incretin hormone. We show that extended and processed peptides differ not only in their binding to the receptor but also in the way the receptor is engaged for activation that leads to differential signaling bias exhibited by these peptides.

Cyanotoxins as the "common suspects" for the Dalmatian pelican (Pelecanus crispus) deaths in a Mediterranean reconstructed reservoir.

Toxic cyanobacterial blooms have been implicated for their negative consequences on many terrestrial and aquatic organisms. Water birds belong to the most common members of the freshwater food chains and are most likely to be affected by the consumption of toxic cyanobacteria as food. However, the contribution of cyanotoxins in bird mortalities is under-studied. The aim of the study was to investigate the likely role of cyanotoxins in a mass mortality event of the Dalmatian pelican (Pelecanus crispus) in the Karla Reservoir, in Greece. Water, scum, tissues and stomach content of dead birds were examined for the presence of microcystins, cylindrospermopsins and saxitoxins by an enzyme-linked immunosorbent assay. High abundances of potential toxic cyanobacterial species and significant concentrations of cyanotoxins were recorded in the reservoir water. All examined tissues and stomach content of the Dalmatian pelicans contained significant concentrations of microcystins and saxitoxins. Cylindrospermopsin concentrations were detected in all tissues except from the brain. Our results suggest that cyanotoxins are a plausible cause for this bird mass mortality episode in the Karla Reservoir.

Microglial activation and progressive brain changes in schizophrenia.

Schizophrenia is a debilitating disorder that typically begins in adolescence and is characterized by perceptual abnormalities, delusions, cognitive and behavioural disturbances and functional impairments. While current treatments can be effective, they are often insufficient to alleviate the full range of symptoms. Schizophrenia is associated with structural brain abnormalities including grey and white matter volume loss and impaired connectivity. Recent findings suggest these abnormalities follow a neuroprogressive course in the earliest stages of the illness, which may be associated with episodes of acute relapse. Neuroinflammation has been proposed as a potential mechanism underlying these brain changes, with evidence of increased density and activation of microglia, immune cells resident in the brain, at various stages of the illness. We review evidence for microglial dysfunction in schizophrenia from both neuroimaging and neuropathological data, with a specific focus on studies examining microglial activation in relation to the pathology of grey and white matter. The studies available indicate that the link between microglial dysfunction and brain change in schizophrenia remains an intriguing hypothesis worthy of further examination. Future studies in schizophrenia should: (i) use multimodal imaging to clarify this association by mapping brain changes longitudinally across illness stages in relation to microglial activation; (ii) clarify the nature of microglial dysfunction with markers specific to activation states and phenotypes; (iii) examine the role of microglia and neurons with reference to their overlapping roles in neuroinflammatory pathways; and (iv) examine the impact of novel immunomodulatory treatments on brain structure in schizophrenia.

Novel GPCR paradigms at the µ-opioid receptor.

UNLABELLED: Opioids, such as morphine, are the most clinically useful class of analgesic drugs for the treatment of acute and chronic pain. However, the use of opioids is greatly limited by the development of severe adverse side effects. Consequently, drug discovery efforts have been directed towards improving the therapeutic profile of opioid-based treatments. Opioid receptors are members of the family of GPCRs. As such, the recent GPCR paradigms of biased agonism and allosterism may provide novel avenues for more effective analgesics. Biased agonism (or functional selectivity) has been described for all the opioid receptor family members. Furthermore, the first allosteric modulators of opioid receptors have very recently been described. However, identification and quantification of biased agonism in a manner that is informative to medicinal chemists and drug discovery programmes still remains a challenge. In this review, we examine the progress, to date, towards identification and quantification of biased agonism and allosterism at the µ-opioid receptor in the context of its implications for the discovery of better and safer analgesics. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.

Biased allosteric modulation at the CaS receptor engendered by structurally diverse calcimimetics.

BACKGROUND AND PURPOSE: Clinical use of cinacalcet in hyperparathyroidism is complicated by its tendency to induce hypocalcaemia, arising partly from activation of calcium-sensing receptors (CaS receptors) in the thyroid and stimulation of calcitonin release. CaS receptor allosteric modulators that selectively bias signalling towards pathways that mediate desired effects [e.g. parathyroid hormone (PTH) suppression] rather than those mediating undesirable effects (e.g. elevated serum calcitonin), may offer better therapies. EXPERIMENTAL APPROACH: We characterized the ligand-biased profile of novel calcimimetics in HEK293 cells stably expressing human CaS receptors, by monitoring intracellular calcium (Ca(2+) i ) mobilization, inositol phosphate (IP)1 accumulation, ERK1/2 phosphorylation (pERK1/2) and receptor expression. KEY RESULTS: Phenylalkylamine calcimimetics were biased towards allosteric modulation of Ca(2+) i mobilization and IP1 accumulation. S,R-calcimimetic B was biased only towards IP1 accumulation. R,R-calcimimetic B and AC-265347 were biased towards IP1 accumulation and pERK1/2. Nor-calcimimetic B was unbiased. In contrast to phenylalkylamines and calcimimetic B analogues, AC-265347 did not promote trafficking of a loss-of-expression, naturally occurring, CaS receptor mutation (G(670) E). CONCLUSIONS AND IMPLICATIONS: The ability of R,R-calcimimetic B and AC-265347 to bias signalling towards pERK1/2 and IP1 accumulation may explain their suppression of PTH levels in vivo at concentrations that have no effect on serum calcitonin levels. The demonstration that AC-265347 promotes CaS receptor receptor signalling, but not trafficking reveals a novel profile of ligand-biased modulation at CaS receptors The identification of allosteric modulators that bias CaS receptor signalling towards distinct intracellular pathways provides an opportunity to develop desirable biased signalling profiles in vivo for mediating selective physiological responses.

Osteocutaneous free flaps for mandibular reconstruction: systematic review of their frequency of use and a preliminary quality of life comparison.

OBJECTIVES: To determine whether the fibula free flap is the most frequently used osteocutaneous flap for mandible reconstruction, and whether it provides quality of life, depression and anxiety advantages. METHODS: A systematic review of the public Medline database was conducted. Thirteen patients who underwent mandibular reconstruction at our hospital centre completed questionnaires to evaluate quality of life, depression and anxiety outcomes. RESULTS: The most frequently used free flaps are those of the fibula (n = 982), radial forearm (n = 201), iliac crest (n = 113), subscapular system (n = 50) and rib-serratus (n = 7). In our patient population, there was a trend towards a better quality of life in those with a fibula free flap. However, patients in this group were significantly younger than patients with other flap types (p = 0.025). Patients with a subscapular system free flap were more depressed (p = 0.031); however, they had large through-and-through defects. CONCLUSION: The flap used most frequently in the literature is the fibula free flap. Comparative quality of life data are lacking, and homogeneous populations should be used to reach significant conclusions.

Engendering biased signalling from the calcium-sensing receptor for the pharmacotherapy of diverse disorders.

The human calcium-sensing receptor (CaSR) is widely expressed in the body, where its activity is regulated by multiple orthosteric and endogenous allosteric ligands. Each ligand stabilizes a unique subset of conformational states, which enables the CaSR to couple to distinct intracellular signalling pathways depending on the extracellular milieu in which it is bathed. Differential signalling arising from distinct receptor conformations favoured by each ligand is referred to as biased signalling. The outcome of CaSR activation also depends on the cell type in which it is expressed. Thus, the same ligand may activate diverse pathways in distinct cell types. Given that the CaSR is implicated in numerous physiological and pathophysiological processes, it is an ideal target for biased ligands that could be rationally designed to selectively regulate desired signalling pathways in preferred cell types.

HPV Prevalence and Prognostic Value in a Prospective Cohort of 255 Patients with Locally Advanced HNSCC: A Single-Centre Experience.

Background. HPV is a positive prognostic factor in HNSCC. We studied the prevalence and prognostic impact of HPV on survival parameters and treatment toxicity in patients with locally advanced HNSCC treated with concomitant chemoradiation therapy. Methods. Data on efficacy and toxicity were available for 560 patients. HPV was detected by PCR. Analysis was performed using Kaplan-Meier survival curves, Fisher's test for categorical data, and log-rank statistics for failure times. Results. Median follow-up was 4.7 years. DNA extraction was successful in 255 cases. HPV prevalence was 68.6%, and 53.3% for HPV 16. For HPV+ and HPV-, median LRC was 8.9 and 2.2 years (P = 0.0002), median DFS was 8.9 and 2.1 years (P = 0.0014), and median OS was 8.9 and 3.1 years (P = 0.0002). Survival was different based on HPV genotype, stage, treatment period, and chemotherapy regimen. COX adjusted analysis for T, N, age, and treatment remained significant (P = 0.004). Conclusions. Oropharyngeal cancer is increasingly linked to HPV. This study confirms that HPV status is associated with improved prognosis among H&N cancer patients receiving CRT and should be a stratification factor for clinical trials including H&N cases. Toxicity of CRT is not modified for the HPV population.

The Concise Guide to PHARMACOLOGY 2013/14: overview.

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties from the IUPHAR database. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full. This compilation of the major pharmacological targets is divided into seven areas of focus: G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors & Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates.

Impact of species variability and 'probe-dependence' on the detection and in vivo validation of allosteric modulation at the M4 muscarinic acetylcholine receptor.

BACKGROUND AND PURPOSE: We recently characterized LY2033298 as a novel allosteric modulator and agonist at M(4) muscarinic acetylcholine receptors (mAChRs). Evidence also suggested a difference in the potency of LY2033298 at rodent relative to human M(4) mAChRs. The current study investigated the basis for the species difference of this modulator and used this knowledge to rationalize its in vivo actions. EXPERIMENTAL APPROACH: LY2033298 was investigated in vitro in CHO cells stably expressing human or mouse M(4) mAChRs, using assays of agonist-induced ERK1/2 or GSK-3α phosphorylation, [(35) S]-GTPγS binding, or effects on equilibrium binding of [(3) H]-NMS and ACh. The in vivo actions of LY2033298 were investigated in a mouse model of amphetamine-induced locomotor activity. The function of LY2033298 was examined in combination with ACh, oxotremorine or xanomeline. KEY RESULTS: LY2033298 had similar affinities for the human and mouse M(4) mAChRs. However, LY2033298 had a lower positive co-operativity with ACh at the mouse relative to the human M(4) mAChR. At the mouse M(4) mAChR, LY2033298 showed higher co-operativity with oxotremorine than with ACh or xanomeline. The different degrees of co-operativity between LY2033298 and each agonist at the mouse relative to the human M(4) mAChR necessitated the co-administration of LY2033298 with oxotremorine in order to show in vivo efficacy of LY2033298. CONCLUSIONS AND IMPLICATIONS: These results provide evidence for species variability when comparing the allosteric interaction between LY2033298 and ACh at the M(4) mAChR, and also highlight how the interaction between LY2033298 and different orthosteric ligands is subject to 'probe dependence'. This has implications for the validation of allosteric modulator actions in vivo.

Male-female differences in the risk of tuberculosis in dialysis patients.

AIM: To define any gender-related differences in the prevalence and risk for tuberculosis (TB) in hemodialysis (HD) patients. METHODS: All active TB cases were recorded during a 36-month follow-up of 272 (193 male and 79 female) HD patients. Entering the study, HD patients were tested with tuberculin and 2,4-dinitrochlorobenzene, and a cell-mediated immunity (CMI) index was estimated. Relative risks (RR) for TB were calculated considering subjects from the background general population as a reference group. The independent effect of age, BMI and tuberculin sensitivity was determined using Cox's proportional hazard model. RESULTS: Female HD patients presented significantly lower CMI indices and rates of positive Mantoux tests, but higher rates of DM, as compared to males. The male:female ratio in TB for the general and HD patients population was 1.8 and 0.6, respectively. There was a significantly lower TB prevalence in male as compared to female HD patients (7.7% vs. 11.3%), and a subsequent female predominance in risk for TB in those HD patients aged <49 and 50-69 years (M:F adjusted relative risk 0.67 and 0.53) was recorded. CONCLUSIONS: In contrast to the general population, there is a female predominance among dialysis TB patients younger than 70 years associated with the coexistence of DM. Female gender should always be considered as a risk factor when evaluating diabetic HD patients for active TB.

Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia.

Current antipsychotics provide symptomatic relief for patients suffering from schizophrenia and related psychoses; however, their effectiveness is variable and many patients discontinue treatment due to side effects. Although the etiology of schizophrenia is still unclear, a leading hypothesis implicates an imbalanced dopaminergic system. Muscarinic acetylcholine (ACh) receptors regulate dopamine levels in key areas of the brain involved in psychosis, with the M(4) subtype emerging as a key regulator of dopaminergic hyperactivity. Unfortunately, no selective small molecule tools exist to provide pharmacological validation of this hypothesis. Here, we describe the discovery of a small molecule modulator, LY2033298, that is highly selective for human M(4) receptors by virtue of targeting an allosteric site on this receptor. Pharmacological assays confirmed the selectivity of LY2033298 for the M(4) receptor and revealed the highest degree of positive allosteric enhancement of ACh potency thus far identified. Radioligand binding assays also show this compound to directly potentiate agonist binding while having minimal effects on antagonist binding. Mutational analysis identified a key amino acid (D(432)) in the third extracellular loop of the human M(4) receptor to be critical for selectivity and agonist potentiation by LY2033298. Importantly, LY2033298 was active in animal models predictive of clinical antipsychotic drug efficacy indicating its potential use as a first-in-class, selective, allosteric muscarinic antipsychotic agent.

Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs.

Finding good drug leads de novo from large chemical libraries, real or virtual, is not an easy task. High-throughput screening is often plagued by low hit rates and many leads that are toxic or exhibit poor bioavailability. Exploiting the secondary activity of marketed drugs, on the other hand, may help in generating drug leads that can be optimized for the observed side-effect target, while maintaining acceptable bioavailability and toxicity profiles. Here, we describe an efficient computational methodology to discover leads to a protein target from safe marketed drugs. We applied an in silico "drug repurposing" procedure for identification of nonsteroidal antagonists against the human androgen receptor (AR), using multiple predicted models of an antagonist-bound receptor. The library of marketed oral drugs was then docked into the best-performing models, and the 11 selected compounds with the highest docking score were tested in vitro for AR binding and antagonism of dihydrotestosterone-induced AR transactivation. The phenothiazine derivatives acetophenazine, fluphenazine, and periciazine, used clinically as antipsychotic drugs, were identified as weak AR antagonists. This in vitro biological activity correlated well with endocrine side effects observed in individuals taking these medications. Further computational optimization of phenothiazines, combined with in vitro screening, led to the identification of a nonsteroidal antiandrogen with improved AR antagonism and marked reduction in affinity for dopaminergic and serotonergic receptors that are the primary target of phenothiazine antipsychotics.

Involvement of the sigma1 (sigma1) receptor in the anti-amnesic, but not antidepressant-like, effects of the aminotetrahydrofuran derivative ANAVEX1-41.

BACKGROUND AND PURPOSE: Tetrahydro-N, N-dimethyl-5, 5-diphenyl-3-furanmethanamine hydrochloride (ANAVEX1-41) is a potent muscarinic and sigma(1) (sigma (1)) receptor ligand. The sigma (1) receptor modulates glutamatergic and cholinergic responses in the forebrain and selective agonists are potent anti-amnesic and antidepressant DRUGS. WE HAVE HERE ANALYSED THE SIGMA (1) COMPONENT IN THE BEHAVIOURAL EFFECTS OF ANAVEX1-41. EXPERIMENTAL APPROACH: Binding of ANAVEX1-41 to muscarinic and sigma (1) receptors were measured using cell membranes. Behavioural effects of ANAVEX1-41 were tested in mice using memory (spontaneous alternation, passive avoidance, water-maze) and antidepressant-like activity (forced swimming) procedures. KEY RESULTS: In vitro, ANAVEX1-41 was a potent muscarinic (M(1)>M(3), M(4)>M(2) with K(i) ranging from 18 to 114 nM) and selective sigma (1) ligand (sigma (1), K(i)=44 nM; sigma (2), K(i)=4 microM). In mice, ANAVEX1-41 failed to affect learning when injected alone (0.03-1 mg kg(-1)), but attenuated scopolamine-induced amnesia with a bell-shaped dose response (maximum at 0.1 mg kg(-1)). The sigma (1) antagonist BD1047 blocked the anti-amnesic effect of ANAVEX1-41 on both short- and long-term memories. Pretreatment with a sigma (1) receptor-directed antisense oligodeoxynucleotide prevented effects of ANAVEX1-41 only in the passive avoidance procedure, measuring long-term memory. ANAVEX1-41 reduced behavioural despair at 30 and 60 mg kg(-1), without involving the sigma (1) receptor, as it was not blocked by BD1047 or the antisense oligodeoxynucleotide. CONCLUSIONS AND IMPLICATIONS: ANAVEX1-41 is a potent anti-amnesic drug, acting through muscarinic and sigma (1) receptors. The latter component may be involved in the enhancing effects of the drug on long-term memory processes.

Bosentan in Eisenmenger syndrome and chronic thromboembolic pulmonary hypertension.

BACKGROUND: Bosentan, a dual endothelin receptor antagonist, has been used for symptomatic improvement of patients with idiopathic pulmonary arterial hypertension (PAH) and specific types of secondary (e.g. scleroderma and human immunodeficiency virus infection) PAH, but its efficacy in patients with congenital heart disease and chronic thromboembolic pulmonary hypertension is still under evaluation. In this study two patients are presented, one with common atrioventricular canal and pulmonary hypertension and the other with recurrent pulmonary thromboembolism; both improved significantly after bosentan administration. MATERIALS AND METHODS: The first patient was a 38-year-old female with trisomy 21, common atrioventricular canal and pulmonary hypertension (Eisenmenger syndrome). The second patient was a 57-year-old male, who was on anticoagulant therapy owing to an episode of pulmonary embolism that had been diagnosed 3 years earlier. Recurrent pulmonary thromboembolism was considered the most probable diagnosis. Chest spiral computed tomography examination excluded pulmonary endarterectomy as a therapeutic approach. At admission, the two patients were on New York Heart Association class IV, diagnosed by progressive rest dyspnea. Bosentan was administered to patients 1 and 2 for 6 and 9 months, respectively (62.5 mg b.i.d. for 4 weeks, then 125 mg b.i.d.). RESULTS: Bosentan therapy resulted in significant clinical improvement in both patients. No hepatic dysfunction nor any other side-effect was observed. CONCLUSIONS: Bosentan could be an effective therapy for pulmonary hypertension owing to congenital heart disease and chronic thromboembolic disease.

Risk of tuberculosis in dialysis patients: association of tuberculin and 2,4-dinitrochlorobenzene reactivity with risk of tuberculosis.

BACKGROUND: Dialysis patients are at increased risk of tuberculosis (TB) and anergy due to attenuated cellular immunity. AIM: To define specific risks of TB in anergic and non-anergic dialysis patients. METHODS: A total of 272 dialysis patients were enrolled in this prospective study over a 36-month follow-up. Entering the study, participants had Mantoux and 2,4-dinitrochlorobenzene skin tests and their cell-mediated immunity (CMI)-index was estimated. Patients were classified as anergic (CMI-index

An asymptomatic pulmonary hilar mass: a case report.

Pulmonary vein varix is a rare benign abnormality, either congenital or acquired, usually presented without symptoms. It is most frequently discovered by chance on a chest radiograph, whereas computed tomography defines the special characteristics of the lesion. Angiography is considered the method of choice for final diagnosis. The authors present the first case of a patient with pulmonary vein varix accompanied by interatrial communication.

Amylin receptors: molecular composition and pharmacology.

Several receptors which bind the hormone AMY (amylin) with high affinity have now been identified. The minimum binding unit is composed of the CT (calcitonin) receptor at its core, plus a RAMP (receptor activity modifying protein). The receptors have been named AMY(1(a)), AMY(2(a)) and AMY(3(a)) in accordance with the association of the CT receptor (CT((a))) with RAMP1, RAMP2 and RAMP3 respectively. The challenge is now to determine the localization and pharmacological nature of each of these receptors. Recent attempts to achieve these aims will be briefly discussed.

G-protein-coupled receptor allosterism: the promise and the problem(s).

Allosteric modulators of G-protein-coupled receptors interact with binding sites that are topographically distinct from the orthosteric site recognized by the receptor's endogenous agonist. Allosteric ligands offer a number of advantages over orthosteric drugs, including the potential for greater receptor subtype selectivity and a more 'physiological' regulation of receptor activity. However, the manifestations of allosterism at G-protein-coupled receptors are quite varied, and significant challenges remain for the optimization of screening methods to ensure the routine detection and validation of allosteric ligands.