High Receptor Concentrations Research Articles

Retinal pathology occurs in stiff-person syndrome.

To evaluate whether structural and functional changes occur in the afferent visual system of patients with stiff-person syndrome (SPS) and whether these changes correlate with disease burden, given the high concentration of γ-aminobutyric acid receptors, which are generally thought to be involved in SPS pathogenesis, in the retina. In this single-center, cross-sectional study, patients with SPS and healthy controls (HCs) underwent optical coherence tomography (OCT), with a subset undergoing high- and low-contrast visual acuity (VA) assessments. Burden of disease was assessed via the number of body regions affected. Individuals with uncontrolled hypertension or comorbid neurologic or ophthalmologic disorders were excluded. Statistical analyses were performed using mixed-effects linear regression models. Thirty-five patients with SPS and 40 age- and sex-matched HCs underwent OCT. A subset of 23 patients with SPS and 28 HCs underwent VA assessments. Relative to HCs, patients with SPS had lower ganglion cell + inner plexiform layer (GCIPL) thicknesses (SPS: 74.36 µm [SD 5.7]; HCs: 76.33 µm [SD 4.2]; p = 0.005), inner nuclear layer thicknesses (SPS: 44.37 µm [SD 2.7]; HCs: 45.18 µm [SD 2.2]; p = 0.042), and 100% (SPS: 53 [SD 9.6]; HCs: 57.5 [SD 6.1]; p = 0.005), 2.5% (SPS: 24.35 [SD 10.1]; HCs: 30.16 [SD 7.7]; p = 0.006), and 1.25% contrast (SPS: 16.41 [SD 10.6]; HCs: 20.84 [SD 8.6]; p = 0.034) letter acuity scores. GCIPL thicknesses correlated with the number of body regions affected in SPS (decrease of 1.25 µm [95% confidence interval, -2.2 to -0.3 µm; p = 0.008] per additional body region affected). Retinal neuronal pathology can occur in SPS. OCT may have utility as a biomarker of disease burden in SPS.

Characterising the diffusion of biological nanoparticles on fluid and cross-linked membranes.

Tracing the motion of macromolecules, viruses, and nanoparticles adsorbed onto cell membranes is currently the most direct way of probing the complex dynamic interactions behind vital biological processes, including cell signalling, trafficking, and viral infection. The resulting trajectories are usually consistent with some type of anomalous diffusion, but the molecular origins behind the observed anomalous behaviour are usually not obvious. Here we use coarse-grained molecular dynamics simulations to help identify the physical mechanisms that can give rise to experimentally observed trajectories of nanoscopic objects moving on biological membranes. We find that diffusion on membranes of high fluidities typically results in normal diffusion of the adsorbed nanoparticle, irrespective of the concentration of receptors, receptor clustering, or multivalent interactions between the particle and membrane receptors. Gel-like membranes on the other hand result in anomalous diffusion of the particle, which becomes more pronounced at higher receptor concentrations. This anomalous diffusion is characterised by local particle trapping in the regions of high receptor concentrations and fast hopping between such regions. The normal diffusion is recovered in the limit where the gel membrane is saturated with receptors. We conclude that hindered receptor diffusivity can be a common reason behind the observed anomalous diffusion of viruses, vesicles, and nanoparticles adsorbed on cell and model membranes. Our results enable direct comparison with experiments and offer a new route for interpreting motility experiments on cell membranes.

Neurotrophic factors in the posterodorsal medial amygdala of male and cycling female rats

The posterodorsal medial amygdala (MePD) has a high concentration of receptors for gonadal hormones, is a sexually dimorphic region and dynamically controls the reproductive behavior of both males and females. Neurotrophic factors can promote dendritic spine remodeling and change synaptic input strength in a region-specific manner. Here, we analyzed the gene and protein expression of brain-derived neurotrophic factor (BDNF), insulin-like growth factor-I (IGF-1), polysialylated neural cell adhesion molecule (PSA-NCAM) and Ephrin-A4 in the MePD of adult males and females in diestrus, proestrus and estrus using real-time qPCR and fluorescent immunohistochemistry. The first approach showed their amplification except for Igf1 and the latter revealed that BDNF, IGF-1, PSA-NCAM and Ephrin-A4 are expressed in the MePD of the adult rats. Protein expression of these neurotrophic factors showed no differences between groups. However, proestrus females displayed a higher number of labelled puncta than males for BDNF expression and diestrus females for IGF-1 expression. In conjunction, results indicate that IGF-1 might be released rather than synthetized in the MePD, and the expression of specific neurotrophic factors varies specifically during proestrus. The dynamic modulation of BDNF and IGF-1 during this cyclic phase is coincident with synaptic changes and spine density remodeling in the MePD, the disinhibition of gonadotrophin secretion for ovulation and the display of sexual behavior.

2346 Primary Neuroendocrine Tumor of the Porta Hepatis in a Patient With Crohn’s Disease

INTRODUCTION: Well-differentiated neuroendocrine tumors (NETs) are rare entities usually of the GI tract and lung. A small subset of NETs have been identified in the biliary tree and liver, and large majorities of these are identified due to high concentrations of somatostatin receptors. We describe the rare case of a patient with Crohn’s disease and a primary porta hepatis NET. CASE DESCRIPTION/METHODS: An 80 year-old female with PMH of Crohn’s disease status post small bowel resection x3 and 30-pack year smoking history presented to clinic with a 5-year history of intermittent RUQ/mid-epigastric pain with known 2 cm liver mass. She denied any weight loss or changes in appetite or bowel habits. Abdominal US revealed a porta hepatis mass with a patent portal vein. Abdominal CT revealed mild diffuse infiltration of the liver and a 4.1 × 3.5 × 3.2 cm porta hepatis mass. The common bile duct measured 10 mm with thickening and irregularity of the antrum, pylorus, and proximal duodenum. There was moderate mesenteric lymphadenopathy. Biopsy of the porta hepatis mass revealed a low/intermediate grade NET of possible GI or pancreatic origin. Urine 5-HIAA was normal, and octreotide scan revealed abnormal activity in the area of the porta hepatis only. EGD revealed H. pylori (+) gastritis, and colonoscopy was normal. The patient underwent exploratory laparotomy revealing biliary invasion and positive metastatic lymph nodes. Open cholecystectomy was performed, and the patient underwent ERCP with common bile duct stent placement. DISCUSSION: Well-differentiated NETs are particularly rare. In a National Cancer Institute series, age-adjusted incidence for non-pancreatic primaries was 4.7 per 100,000. Most primary NETs are located in the GI tract (55%) and bronchopulmonary system (30%) and tend to metastasize to the liver. Patients may experience pain, jaundice, early satiety, flushing, or diarrhea. Our patient’s only complaint was pain. Despite an extensive workup to stage the cancer and identify a potential primary, no additional culprit lesion was identified. Immunohistochemical staining and/or molecular classifier assays of the specimen can be helpful to identify the primary site but are not definitive. We believe this is a primary hepatic lesion which is very rare. Metastasis to the biliary tree and hilar lymph nodes portends a poorer prognosis. Our patient was started on Somatuline. Somatostatin analogs are highly effective in controlling symptoms associated with advanced GI NETs.

Therapeutic Potential of “Exosomes Derived Multiple Allogeneic Proteins Paracrine Signaling: Exosomes d-MAPPS” is Based on the Effects of Exosomes, Immunosuppressive and Trophic Factors

Abstract Due to their differentiation capacity and potent immunosuppressive and pro-angiogenic properties, mesenchymal stem cells (MSCs) have been considered as new therapeutic agents in regenerative medicine. Since most of MSC-mediated beneficent effects are a consequence of their paracrine action, we designed MSC-based product “Exosomes Derived Multiple Allogeneic Proteins Paracrine Signaling (Exosomes d-MAPPS), which activity is based on MSCs-derived growth factors and immunomodulatory cytokines capable to attenuate inflammation and to promote regeneration of injured tissues. Interleukin 1 receptor antagonist (IL-1Ra) and IL-27 were found in high concentrations in Exosomes d-MAPPS samples indicating strong anti-inflammatory and immunosuppressive potential of Exosomes d-MAPPS. Additionally, high concentrations of vascular endothelial growth factor receptor (VEGFR1) and chemokines (CXCL16, CCL21, CXCL14) were noticed at Exosomes d-MAPPS samples suggesting their potential to promote generation of new blood vessels and migration of CXCR6, CCR7 and CXCR4 expressing cells. Since all proteins which were found in high concentration in Exosomes d-MAPPS samples (IL-1Ra, CXCL16, CXCL14, CCL21, IL-27 and VEGFR1) are involved in modulation of lung, eye, and synovial inflammation, Exosomes d-MAPPS samples were prepared as inhalation and ophthalmic solutions in addition to injection formulations; their application in several patients suffering from chronic obstructive pulmonary disease, osteoarthritis, and dry eye syndrome resulted with significant improvement of biochemical and functional parameters. In conclusion, Exosomes d-MAPPS, due to the presence of important anti-inflammatory, immunomodulatory, and pro-angiogenic factors, represents potentially new therapeutic agent in regenerative medicine that should be further tested in large clinical studies.

Effects of combined oral contraceptives on the sexuality and quality of life of women

Aim. Examine the impact of combined oral contraceptive on sexuality and the quality of women’s life. Materials and methods. The article presents a review of Electronic literature databases MEDLINE, PubMed, EMBASE, Cochrane Library and Elibrary. Results. Since its first introduction in the 1960s, hormonal contraception has been widely used as a highly effective birth control method. However, the hormonal components of oral contraceptives affect the neuroendocrine system of women, exerting various effects on mood, libido, on sexuality and quality of life in general. Based on literature data the effect of contraception on sexuality, the physiological and emotional state of women are various. It is known that the hormonal supplementation of sexual desire is associated with ovarian hormones. At the same time, a high concentration of estrogen and testosterone receptors has been determined in the hypothalamus, which controls sexual function and mood. The mechanisms to implement the effects of androgen and progesterone on sexual desire are ambiguous. It was found a positive relationship between a sexual interest, sexual response, sexual fantasy, frequency of sexual intercourse and a testosterone level. At the same time, it is known that estradiol can increase the ability of women to orgasmic response and sexual satisfaction by acting on specific brain structures. Conclusion. The effect of contraception on women’s sexual life is an important factor when choosing a method of contraception and an integral part in the obstetrician-gynecologist’s practice, which requires further research in this direction.

Design of Finger Bending Measurement System

Human finger is a flexible, long and thin extension of the hand commonly referred to as the digits. The fingers on the hands correspond to the toes of the feet. Humans have five fingers on each hand and a significant feature in humans is the opposable thumb. Apart from the flexibility of the human fingers which make it such a useful appendage of the hand, there is a high concentration of receptors in the finger which means it is an important sense organ. The boring training processes and a long therapy session that often cause patients to lose motivation to continue therapy may cause the patient to discontinue the rehabilitation process. A sensorized finger bending glove is a device that can be used to measure the level of rehabilitation process with respect to the finger movements using a glove that consists of a flex sensor, Liquid Crystal Display (LCD) and Light Emitting Diode (LED) for a fracture finger patient. The aim of this work is to develop a device that enhances the life of patient to fulfil their life activities such as lifting, gripping and grasping. This glove consists of five flex sensors that are placed on all fingers of glove. Then, these sensors will be used as an input to control the movement of fingers using Arduino Mega. Arduino acts as an interface between the flex sensors with an indicator which are LED and LCD. The glove is controlled based on the movement of flex sensor. The result shows that a sensorized glove can be controlled by patient‟s fingers when there is no bending (0°), red LED will light up. The blue and green LED will light up when patient can bend their fingers at 45° and 90° respectively.

Androgen treatment effects on hippocampus structure in boys with Klinefelter syndrome

Klinefelter syndrome (KS, 47,XXY) is the most common sex chromosome aneuploidy in males. A variety of complex clinical needs is associated with KS, including physical, cognitive and psychosocial impairments. Standard treatment for KS consists of androgen replacement therapy in adolescence to offset testosterone deficiency. Such treatment has a beneficial effect on the physical and behavioral manifestations of this syndrome. Whether androgen supplementation has a significant influence on the brain, however, is unknown. In the current study, we examined regional gray matter volume in boys with KS to assess whether treatment with oxandrolone, a synthetic hormone analog of testosterone, was associated with structural changes in the brain. Specifically, we focused our investigation on the hippocampus, given (1) its involvement in KS, and (2) the high concentration of androgen receptors found in this region. Structural magnetic resonance imaging data was acquired from a subsample of boys who completed a 2-year double-blind clinical trial in which patients were randomized to treatment with oxandrolone or to placebo, as well as from a sample of typically developing (TD) boys. Group differences in hippocampal volume were examined. A significant main effect of group was observed. Pairwise comparisons indicated smaller hippocampal volume in the placebo group relative to the oxandrolone group, as well as smaller volume in the placebo group relative to the TD control group. No difference in volume was observed between the treatment and TD groups. Moreover, across KS subgroups, a significant positive association was observed between hippocampus volume and performance on a spatial memory task, indicating treatment-based changes in brain structure may underlie cognitive change. These findings confirm prior reports implicating a role of the hippocampus in KS and are important in extending previous research by demonstrating a significant effect of androgens on brain structure.

Cloning, Expression, Purification and Characterization of Oligomeric States of the Native 5HT2A G-Protein-Coupled Receptor.

The 5HT2A G-Protein Coupled Receptor (GPCR) is an important family of receptors involved in an array of neuromodulatory functions. Their dysregulation has been implicated in a number of psychiatric diseases. In spite of the importance of this GPCR, high resolution structure and mechanistic details of its function is unknown. Cholesterol plays an important role in the function of many receptors and reduced cholesterol levels can lead to disruption of serotonergic pathways. However, the role of cholesterol in the formation of GPCR oligomers has not been previously shown for this receptor. Given that receptor dimers have been shown to be the functional unit of this receptor, it is important to investigate the effect of cholesterol in the oligomeric state of 5HT2A receptor. The main objective of this work is to clone, over-express and purify the 5HT2A receptor and investigate the effect of cholesterol in its oligomer formation. The 5HT2A receptor (5HT2AR) DNA construct was subcloned into pFastBac-HT vector and the purified bacmid was used to transfect healthy Sf9 cells. After subsequent passages, a high titer baculovirus was used for over-expression in Sf9 cells. To verify whether the over-expressed receptor was localized in the membrane or cytosolic fraction, cells with and without baculoviral infection were analyzed by immunocytochemistry. Subsequently, the over-expression conditions required to obtain sufficient quantity of the receptor was optimized followed by the optimization of the purification conditions. Finally, the culture was scaled up and the receptor was purified by affinity chromatography. The over-expression of the receptor was checked by Western blotting and purity was analyzed by Coomassie stained SDS PAGE. Cryo-electron microscopy experiments were performed on the purified receptor in presence and absence of cholesterol and at multiple concentrations to rule out any concentration dependent effect on the oligomer formation. Immunocytochemistry experiments showed prominent nuclear staining; however, bright green staining along the cell membrane was observed only for the infected cells, suggesting appropriate trafficking of majority of the over-expressed receptors to the cell membrane. Results of cryoelectron microscopy show that the receptor with cholesterol had particles that were bigger in size (~11 - 12 nm) compared to the dimension of known GPCR homologs. In contrast, the receptor after removal of cholesterol revealed a uniform distribution of smaller particles (~5 - 6 nm) that is approximately half the size of 5HT2AR particles with cholesterol. Comparing the 2D average views of detergent-encapsulated 5HT2AR particles with the overall dimensions of other 5HT receptor analogs, we show that while a 5HT2AR dimer more closely matches the dimensions of particles with CHS, only a monomer can be fit to particles without CHS. Importantly, even at higher receptor concentration and particle density, the size for 5HT2AR particles without CHS remains the same, suggesting that dimerization is unlikely an effect of concentration. Our results indicated that 5HT2A receptor primarily forms a dimer in presence of cholesterol whereas it predominantly forms a monomer when cholesterol is removed.

Abstract 111: A Kidney Targeted Epoxyeicosatrienoic Acid Analog, EET-F01, Reduces Cisplatin-induced Nephrotoxicity

Epoxyeicosatrienoic acid (EET) analogs have exceptional therapeutic potential to combat cardiovascular and kidney diseases. EET analogs combat damage in acute and chronic kidney disease models. Biological actions attributed to EET analogs such as vasodilation, anti-inflammation, anti-apoptosis, and anti-fibrosis are ideally suited to treat kidney diseases. Although EET analogs have performed well in several in vivo models, targeted delivery of EET analogs to the kidney can be reasonably expected to reduce the level of drug needed to achieve a therapeutic effect in the kidney and obviate possible side effects. For EET analog kidney-targeted delivery, we conjugated an EET analog to folic acid because there is a high concentration of folate receptors in renal tissue. The EET analog was conjugated to folic acid via a PEG-diamine linker. Next, we compared the kidney targeted EET analog, EET-F01, to a well-studied EET analog, EET-A. EET-A or EET-F01 was infused i.v. (10mg/kg/hr) for 6 hours via the rat jugular vein. Plasma and kidney tissue were collected and EET-A or EET-F01 measured by LC-MS-MS. EET-A plasma level was 1.6 ng/mL, but EET-A was undetectable in the kidney. On the other hand, EET-F01 was 6.5 ng/mL in plasma and 26.7 ng/mL in kidney tissue. These data demonstrate that EET-F01 targets the kidney. Experiments were conducted to compare EET-F01 and EET-A to decrease cisplatin-induced nephrotoxicity. A single injection of cisplatin (7 mg/kg ip) was administered to WKY rats treated with vehicle, EET-A (10 mg/kg ip) or EET-F01 (20 mg/kg or 2 mg/kg ip) for five days. Cisplatin increased BUN (125 ± 11 mg/dL) and NAG (12 ± 4 IU/L) compared to control (36 ± 9 mg/dL and 4 ± 1 IU/L). EET-F01 was as effective as EET-A in decreasing BUN, NAG, and renal histological injury five days following cisplatin administration. Despite it almost 2x-greater molecular weight compared with EET-A, EET-F01 was effective in lowering BUN and NAG at 20 mg/kg/d and at a 10-fold lower dose of 2 mg/kg/d. These data clearly demonstrate that EET-F01 targets the kidney and allows for a lower effective dose. In conclusion, we have developed a kidney targeted EET analog, EET-F01, that demonstrates excellent potential as a therapeutic for kidney diseases.

A diffusion weighted imaging study of basal ganglia in schizophrenia

Objectives: Several magnetic resonance imaging (MRI) studies provided evidence of selective brain abnormalities in schizophrenia, both in cortical and subcortical structures. Basal ganglia are of particular interest, given not only the high concentration of dopaminergic neurons and receptors, but also for their crucial role in cognitive functions, commonly impaired in schizophrenia. To date, very few studies explored basal ganglia using diffusion imaging, which is sensitive to microstructural organization in brain tissues. The aim of our study is to explore basal ganglia structures with diffusion imaging in a sizeable sample of patients affected by schizophrenia and healthy controls.Methods: We enrolled 52 subjects affected by schizophrenia according to DMS-IV-R criteria and 46 healthy controls. Diffusion weighted images were obtained using a 1.5 Tesla scanner and apparent diffusion coefficient (ADC) values were determined in axial and coronal sections at the level of basal ganglia.Results: Patients affected by schizophrenia showed a significantly higher ADC compared to healthy controls in the left anterior lenticular nucleus (F = 3.9, p = .05). A significant positive correlation between right anterior lenticular nucleus and psychotropic dosages was found (r = 0.4, p = .01).Conclusions: Our study provides evidence of lenticular nucleus microstructure alterations in schizophrenia, potentially sustaining cognitive and motor deficits in schizophrenia.Key pointsThe basal ganglia structures was explored with diffusion imaging in a sizeable sample of patients affected by schizophrenia and healthy controls.Patients affected by schizophrenia showed a significantly higher ADC compared to healthy controls in the left anterior lenticular nucleus.Our study provides evidence of lenticular nucleus microstructure alterations in schizophrenia, potentially sustaining cognitive and motor deficits in schizophrenia.

The serum concentration of soluble interleukin-2 receptor in patients with Kawasaki disease.

Kawasaki disease is a febrile disease of childhood that is associated with increased inflammatory cytokines and immunoregulatory abnormalities. While the serum concentrations of soluble IL-2 receptor can change under such pathologies, the relevance of the soluble IL-2 receptor concentration in patients with Kawasaki disease has not been specified. We aimed to summarize the existing studies that reported the soluble IL-2 receptor concentrations in patients with Kawasaki disease. Original articles that were published up to July 2016 were collected using a PubMed/Medline-based search engine. A total of nine articles that reported the serum soluble IL-2 receptor concentrations in acute-phase Kawasaki disease were eligible. All of the articles described a high soluble IL-2 receptor concentration in patients with Kawasaki disease relative to the level of controls or the reference range. Two of five articles on patients with coronary artery aneurysms described a significantly higher soluble IL-2 receptor concentration in patients with coronary artery aneurysms than patients without. Two articles on patients with intravenous immunoglobulin therapy described a significant decrease of the soluble IL-2 receptor concentration after the therapy. Accordingly, the serum soluble IL-2 receptor can be a potent marker of disease activity and therapeutic effects in patients with Kawasaki disease; further studies are thus warranted for its use in the clinical setting.

Brain connectivity aberrations in anabolic-androgenic steroid users.

Sustained anabolic-androgenic steroid (AAS) use has adverse behavioral consequences, including aggression, violence and impulsivity. Candidate mechanisms include disruptions of brain networks with high concentrations of androgen receptors and critically involved in emotional and cognitive regulation. Here, we tested the effects of AAS on resting-state functional brain connectivity in the largest sample of AAS-users to date. We collected resting-state functional magnetic resonance imaging (fMRI) data from 151 males engaged in heavy resistance strength training. 50 users tested positive for AAS based on the testosterone to epitestosterone (T/E) ratio and doping substances in urine. 16 previous users and 59 controls tested negative. We estimated brain network nodes and their time-series using ICA and dual regression and defined connectivity matrices as the between-node partial correlations. In line with the emotional and behavioral consequences of AAS, current users exhibited reduced functional connectivity between key nodes involved in emotional and cognitive regulation, in particular reduced connectivity between the amygdala and default-mode network (DMN) and between the dorsal attention network (DAN) and a frontal node encompassing the superior and inferior frontal gyri (SFG/IFG) and the anterior cingulate cortex (ACC), with further reductions as a function of dependency, lifetime exposure, and cycle state (on/off).

Antibodies Can Exploit Molecular Crowding to Bind New Antigens at Noncanonical Paratope Positions

AbstractDespite having limited number of antibody molecules, it is still unclear how immune system recognizes surfeit of antigens. A novel mechanism of antigen recognition was deciphered from the crystallographic analysis of scFv 2D10 bound to disaccharide moiety. High‐resolution crystal structure of the complex reveals unusual binding of scFv 2D10 with α1‐6 mannobiose resembling supramolecular assemblies. The disaccharide interacts with the scFv 2D10 at two sites independent of canonical sugar binding positions, in two chemically distinct environments. At site A, α1‐6 mannobiose lies on two‐fold symmetry axis interacting through π‐stacking and water network. However, at site B, α1‐6 mannobiose exists in two orientations related by quasi‐symmetry with direct hydrogen bonds. Although individual one on one interactions are low at both sites, symmetry related molecules contribute significantly for stable binding of the disaccharides, indicated by 2–4 fold lower binding energies. These interactions are facilitated due to relatively high concentrations of receptor and ligand. We propose that the molecular crowding leading to supramolecular associations acts as a specificity determinant and could be naturally exploited to bind diverse antigens. This previously uncharacterized property will considerably enhance the recognition repertoire of antibodies and therefore allows the humoral response to deal with the threat posed by plethora of antigens.

Enzymatic Activity of the Scaffold Protein Rapsyn for Synapse Formation

Neurotransmission is ensured by a high concentration of neurotransmitter receptors at the postsynaptic membrane. This is mediated by scaffold proteins that bridge the receptors with cytoskeleton. One such protein is rapsyn (receptor-associated protein at synapse), which is essential for acetylcholine receptor (AChR) clustering and NMJ (neuromuscular junction) formation. We show that the RING domain of rapsyn contains E3 ligase activity. Mutation of the RING domain that abolishes the enzyme activity inhibits rapsyn- as well as agrin-induced AChR clustering in heterologous and muscle cells. Further biological and genetic studies support a working model where rapsyn, a classic scaffold protein, serves as an E3 ligase to induce AChR clustering and NMJ formation, possibly by regulation of AChR neddylation. This study identifies a previously unappreciated enzymatic function of rapsyn and a role of neddylation in synapse formation, and reveals a potential target of therapeutic intervention for relevant neurological disorders.

Switch-like surface binding of competing multivalent particles

Multivalent particles competing for binding on the same surface can exhibit switch-like behaviour, depending on the concentration of receptors on the surface. When the receptor concentration is low, energy dominates the free energy of binding, and particles having a small number of strongly-binding ligands preferentially bind to the surface. At higher receptor concentrations, multivalent effects become significant, and entropy dominates the binding free energy; particles having many weakly-binding ligands preferentially bind to the surface. Between these two regimes there is a “switch-point”, at which the surface binds the two species of particles equally strongly. We demonstrate that a simple theory can account for this switch-like behaviour and present numerical calculations that support the theoretical predictions. We argue that binding selectivity based on receptor density, rather than identity, may have practical applications.

Schizophrénie et addictions : les liaisons dangereuses

A majority of patients with schizophrenia are comorbid with addictions. Addictive comorbidities impact prognosis and outcome of the disease. They result in diagnostic and therapeutic challenges for caregivers since they are causing a considerable proportion of cases of non-response to treatment. These are the main causes of disability among adolescents and young adults patients in the world and their socio economic impact represents a growing challenge for all health systems. Double diagnosis are more frequent in homeless populations and represent a major risk factor of suicidal behavior. Consumption of psychoactive substances, Alcohol and illicit drugs contributes to excess mortality of schizophrenic patients to both natural and unnatural causes. Many factors have been identified to explain the reasons for this high comorbidity. Some genetic, social and economic factors are common between schizophrenia and addiction. Psychological and behavioral factors have mainly been studied in relation to the specific links between schizophrenia and cannabis. Two complementary hypotheses are argued, self-medication and damage hypothesis. Advances in brain imaging have shown that chronic cannabis use alters the morphology of the brain regions whith high concentration of cannabinoid receptors like hippocampus and amygdala. Though effects of cannabis may interact with other vulnerability factors of schizophrenia. The management of patients with schizophrenia and addiction requires clear diagnosis identification and integrated care with an efficient coordination between professionals. In regard of the impact on those who suffer, their entourages and the medical and economic impact of these disorders, measures on organizational care setting and promotion of research and evaluation are needed.

The impact of ADHD persistence, recent cannabis use, and age of regular cannabis use onset on subcortical volume and cortical thickness in young adults

BackgroundBoth Attention Deficit Hyperactivity Disorder (ADHD) and chronic cannabis (CAN) use have been associated with brain structural abnormalities, although little is known about the effects of both in young adults. MethodsParticipants included: those with a childhood diagnosis of ADHD who were CAN users (ADHD_CAN; n=37) and non-users (NU) (ADHD_NU; n=44) and a local normative comparison group (LNCG) who did (LNCG_CAN; n=18) and did not (LNCG_NU; n=21) use CAN regularly. Multiple regressions and MANCOVAs were used to examine the independent and interactive effects of a childhood ADHD diagnosis and CAN group status and age of onset (CUO) on subcortical volumes and cortical thickness. ResultsAfter controlling for age, gender, total brain volume, nicotine use, and past-year binge drinking, childhood ADHD diagnosis did not predict brain structure; however, persistence of ADHD was associated with smaller left precentral/postcentral cortical thickness. Compared to all non-users, CAN users had decreased cortical thickness in right hemisphere superior frontal sulcus, anterior cingulate, and isthmus of cingulate gyrus regions and left hemisphere superior frontal sulcus and precentral gyrus regions. Early cannabis use age of onset (CUO) in those with ADHD predicted greater right hemisphere superior frontal and postcentral cortical thickness. DiscussionYoung adults with persistent ADHD demonstrated brain structure abnormalities in regions underlying motor control, working memory and inhibitory control. Further, CAN use was linked with abnormal brain structure in regions with high concentrations of cannabinoid receptors. Additional large-scale longitudinal studies are needed to clarify how substance use impacts neurodevelopment in youth with and without ADHD.

Expression and physiology of opioid receptors in the gastrointestinal tract.

Stimulation of opioid receptors elicits analgesic effect not only in the central nervous system, but also in the gastrointestinal tract, where a high concentration of opioid receptors can be found within the enteric nervous system as well as muscular and immune cells. Along with antinociception, opioid receptors in the stomach and intestine relay signals crucial for secretory and motor gastrointestinal function. The review focuses on the utility of opioid receptor antagonists, which is generally contributing to the management of postoperative ileus and opioid bowel dysfunction in chronic pain patients nonetheless, opioid receptor antagonists can also be useful in the treatment of irritable bowel syndrome and chronic idiopathic constipation. The study also discusses several antidiarrheal opioid agonists, as well as opioids and opioid mimetics encompassing the concept of ligand-biased agonism and truncated opioid receptor splice variants. Good understanding of the localization and the role of opioid receptors is vital for regulation of various pathophysiological processes in the gastrointestinal tract and may simultaneously provide a tempting approach in eliminating adverse effects related to centrally acting opioids.

The Homozygous Hemoglobin EE Genotype and Chronic Inflammation Are Associated with High Serum Ferritin and Soluble Transferrin Receptor Concentrations among Women in Rural Cambodia

Background: Ferritin and soluble transferrin receptor (sTfR) concentrations are commonly used to assess iron deficiency (ID); however, they are influenced by multiple factors.Objectives: We assessed associations between numerous variables and both ferritin and sTfR concentrations in Cambodian women and compared ID prevalence through the use of study-generated correction factors (CFs) for ferritin with those from a published meta-analysis.Methods: Venous blood from 450 women (aged 18–45 y) was assessed for hemoglobin (Hb), ferritin, sTfR, retinol binding protein, folate, vitamin B-12, C-reactive protein, α-1 acid glycoprotein (AGP), and genetic Hb disorders. Linear regression was used to calculate geometric mean ratios (95% CIs) for ferritin and sTfR concentrations.Results: The variant Hb EE genotype was associated with 50% (14%, 96%) and 51% (37%, 66%) higher geometric mean ferritin and sTfR concentrations, respectively, than was the normal Hb AA genotype; a 1-g/L increase in AGP was associated with 99% (50%, 162%) and 48% (33%, 64%) higher concentrations in the same variables, respectively. ID prevalence in nonpregnant women (n = 420) was 2% (n = 9) with the use of ferritin <15 μg/L and 18% (n = 79) with the use of sTfR >8.3 mg/L as criteria. ID prevalence with the use of sTfR was higher in women with the Hb EE genotype (n = 17; 55%) than in those with the Hb AA genotype (n = 20; 10%); and in women with the Hb AA genotype and chronic inflammation (n = 10; 18%) than in that group of women without chronic inflammation (n = 10; 7%) (P < 0.05). No differences in ID prevalence were found with the use of ferritin between women with Hb EE and AA genotypes (P = 1.0) or by chronic inflammation status (P = 0.32). There were no differences in mean ferritin concentrations among all 450 women when study-generated CFs were compared with those from the meta-analysis (P = 0.87).Conclusions: Compared with sTfR, ferritin concentrations appear to reflect more accurately true ID in rural Cambodian women. The CFs from a published meta-analysis were appropriate for use in this population with a high prevalence of Hb disorders and inflammation.