Aromatic L-Amino Acid Decarboxylase Deficiency Is a Cause of Long-Fasting Hypoglycemia

Objective/Context: Long-fasting hypoglycemia in children may be induced by neurotransmitter disorders. Case Report: A 5-year-old girl with a medical history of chronic diarrhea presented three episodes of severe hypoglycemia (20 mg/dL) between ages 3 and 5 years. She became pale and sweaty with hypothermia (33.5°C), bradycardia (45 bpm), and acidosis and presented a generalized seizure. During the 17-hour fast test performed to determine the etiology of her hypoglycemia, insulin and C-peptide were appropriately low, and human GH, IGF-I, cortisol, amino acids, and acylcarnitines were in the usual range for fasting duration. However, the presence of vanillactic and vanilpyruvic acids in urine led us to investigate the metabolism of dopamine and serotonin in the cerebrospinal fluid. Indeed, these results indicated an aromatic L-amino acid decarboxylase deficiency that impairs the synthesis of serotonin, dopamine, and catecholamines. The diagnosis was confirmed by the low aromatic L-amino acid decarboxylase (AADC) enzyme activity in plasma (5 pmol/min/mL; reference value, 20–130) and the presence of two heterozygous mutations, c.97G>C (p.V33L, inherited from her father) and c.1385G>C (p.R462P, inherited from her mother) in the DCC gene. She was supplemented with pyridoxine and raw cornstarch (1 g/kg) at evening dinner to reduce the night fast. The episodes of hypoglycemia and the chronic diarrhea were suppressed. Conclusion: Here is the first case report of long-fasting hypoglycemia due to a nontypical AADC deficiency. Hypoglycemia was severe, but the other neurological clinical hallmarks present in AADC-deficient patients were mild to moderate. Thus, neurotransmitter disorders should be considered in any patients presenting hypoglycemia with urine excretion of vanillactic acid

PROTECCIÓN QUE EL ESTADO MEXICANO DEBE BRINDAR AL ADULTO MAYOR RESPECTO DE SU PATRIMONIO: LOS JUZGADORES DEL ESTADO DE MÉXICO

La reforma constitucional de 2011, colocó en el centro del sistema jurídico mexicano a los Derechos Humanos así, el artículo 1° constitucional señala: “Todas las autoridades, en el ámbito de sus competencias, tienen la obligación de promover, respetar, proteger y garantizar los derechos humanos de conformidad con los principios de universalidad, interdependencia, indivisibilidad y progresividad. En consecuencia, el Estado deberá prevenir, investigar, sancionar y reparar las violaciones a los derechos humanos, en los términos que establezca la ley.” Para efectos de que los adultos mayores estén en aptitud de dinamizar sus derechos y estos no queden sólo en el terreno de ideal normativo, el Estado mexicano, como garante de los derechos de los gobernados debe ir adaptando las normas protectoras conforme se presenten cambios sociales. El derecho debe ser tan dinámico como la propia sociedad, la normatividad debe revisarse en forma permanente y el legislador debe de realizar las adecuaciones pertinentes para que los derechos se dinamicen en términos de efectividad. Respecto de la protección del patrimonio de los adultos mayores es una prioridad revisar no sólo la armónica normatividad que ha de aplicar el juzgador, ya que en el diario quehacer jurisdiccional se perciben las más variadas acciones que ejercen fundamentalmente familiares para despojar de sus bienes a los adultos mayores, sin que ellos reciban beneficio directo alguno.La presente tesis muestra a través de su desarrollo el marco jurídico existente en cuanto a la protección del patrimonio del hombre de la tercera edad en el estado de México. En conjunto con la información del párrafo anterior se muestran datos estadísticos acerca de esta rama de la población (las personas de la tercera edad), así como del sistema judicial en materia civil que existe en el estado de México para la protección de sus patrimonio

Efficacy of Anakinra for Various Types of Crystal-Induced Arthritis in Complex Hospitalized Patients: A Case Series and Review of the Literature

International audienceBackground. There are few data on anakinra use after failure of conventional medications for crystal-induced peripheral arthritis and/or crowned dens syndrome among complex hospitalized patients. Methods. We retrospectively analyzed the outcome of six patients affected with subacute crystal-induced arthritis who had received anakinra in second or third line therapy, including three patients with crowned dens syndrome and three others with gouty arthritis. Patients' comorbidities, reasons for anakinra use and associated drugs, and outcomes were recorded. Results. All patients presented with elevated inflammatory syndrome, systemic symptoms with poly/oligoarthritis. Except for absolute contraindications, all patients were previously treated with full or decreased dose of NSAID, colchicine, and/or glucocorticoids, with unsatisfactory response. All three gouty patients exhibited complete responses in all acute involvements under anakinra within 3 to 5 days, including one of them who needed the reintroduction of colchicine treatment that was previously unsuccessful. Crowned dens syndrome patients, including two with pseudogout and one with subacute hydroxyapatite deposition disease, needed 9 to 11 days to achieve complete response. Tolerance to anakinra was good. Conclusion. In case series of complex hospitalized patients, anakinra showed good activity in crowned dens syndrome and associated crystal-induced peripheral arthritis, with longer treatment duration than in gouty arthritis

A Cannabinoid CB 1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects

Peer reviewedPostprin

N-Oleoyl-glycine reduces nicotine reward and withdrawal in mice.

Cigarette smokers with brain damage involving the insular cortex display cessation of tobacco smoking, suggesting that this region may contribute to nicotine addiction. In the present study, we speculated that molecules in the insular cortex that are sensitive to experimental traumatic brain injury (TBI) in mice might provide leads to ameliorate nicotine addiction. Using targeted lipidomics, we found that TBI elicited substantial increases of a largely uncharacterized lipid, N-acyl-glycine, N-oleoyl-glycine (OlGly), in the insular cortex of mice. We then evaluated whether intraperitoneal administration of OlGly would alter withdrawal responses in nicotine-dependent mice as well as the rewarding effects of nicotine, as assessed in the conditioned place preference paradigm (CPP). Systemic administration of OlGly reduced mecamylamine-precipitated withdrawal responses in nicotine-dependent mice and prevented nicotine CPP. However, OlGly did not affect morphine CPP, demonstrating a degree of selectivity. Our respective in vitro and in vivo observations that OlGly activated peroxisome proliferator-activated receptor alpha (PPAR-α) and the PPAR-α antagonist GW6471 prevented the OlGly-induced reduction of nicotine CPP in mice suggests that this lipid acts as a functional PPAR-α agonist to attenuate nicotine reward. These findings raise the possibility that the long chain fatty acid amide OlGly may possess efficacy in treating nicotine addiction

The analgesic-like properties of the alpha7 nAChR silent agonist NS6740 is associated with non-conducting conformations of the receptor

The alpha 7 nicotinic acetylcholine receptor (nAChR) is a promising drug target for a number of neurological disorders including chronic pain and inflammatory diseases. Since alpha 7 can function as a ligand-gated ion channel, drug development initially focused on ligands that were selective activators of the alpha 7 ion channel. However, the best alpha 7 drugs for chronic pain and inflammation indications may not be ion channel activators but rather "silent agonists", which bind to the receptor but preferentially induce non-conducting states that modulate signal transduction in non-neuronal cells. One such compound is NS6740. We show that NS6740 selectively induces prolonged desensitization of alpha 7 nAChRs. There are two forms of alpha 7 desensitization that can be distinguished by their sensitivity to the positive allosteric modulators (PAMs). At high concentrations, NS6740 preferentially induces PAM-insensitive desensitization, which over the course of several minutes reverts to the sensitive form. NS6740 was tested in several pain models after in vivo administration in the mouse. Although it had no effects in acute thermal pain, NS6740 induced significant dose- and time-dependent antinociceptive activity in formalin- and acetic acid-induced nociceptive behaviors as well as in the chronic constrictive nerve injury (CCI) model for neuropathic pain. The antinociceptive activity of NS6740 in these models was alpha 7-dependent. In addition, NS6740 administration reversed pain-induced aversion, an important affective component of pain. The time and concentration dependence of the effects were consistent with NS6740 induction of PAM-insensitive non-conducting states, suggesting that signal transduction required for analgesia is accomplished by alpha 7 receptors in that conformation.VCU Massey Cancer Center (A-35337)United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Drug Abuse (NIDA) European Commission (DA032246)United States Department of Health & Human Services National Institutes of Health (NIH) - USA (GM57481)United States Department of Health & Human Services National Institutes of Health (NIH) - USA (DA027113)United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of General Medical Sciences (NIGMS) (R01GM057481)United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Drug Abuse (NIDA) European Commission (R01DA032246)United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Drug Abuse (NIDA) European Commission (R01DA012610)United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Drug Abuse (NIDA) European Commission (R03DA027113

Diacylglycerol lipase beta inhibition reverses nociceptive behaviour in mouse models of inflammatory and neuropathic pain

Background and PurposeInhibition of diacylglycerol lipase (DGL) prevents LPS-induced pro-inflammatory responses in mouse peritoneal macrophages. Thus, the present study tested whether DGL inhibition reverses allodynic responses of mice in the LPS model of inflammatory pain, as well as in neuropathic pain models. Experimental ApproachInitial experiments examined the cellular expression of DGL and inflammatory mediators within the LPS-injected paw pad. DAGL- (-/-) mice or wild-type mice treated with the DGL inhibitor KT109 were assessed in the LPS model of inflammatory pain. Additional studies examined the locus of action for KT109-induced antinociception, its efficacy in chronic constrictive injury (CCI) of sciatic nerve and chemotherapy-induced neuropathic pain (CINP) models. Key ResultsIntraplantar LPS evoked mechanical allodynia that was associated with increased expression of DGL, which was co-localized with increased TNF- and prostaglandins in paws. DAGL- (-/-) mice or KT109-treated wild-type mice displayed reductions in LPS-induced allodynia. Repeated KT109 administration prevented the expression of LPS-induced allodynia, without evidence of tolerance. Intraplantar injection of KT109 into the LPS-treated paw, but not the contralateral paw, reversed the allodynic responses. However, i.c.v. or i.t. administration of KT109 did not alter LPS-induced allodynia. Finally, KT109 also reversed allodynia in the CCI and CINP models and lacked discernible side effects (e.g. gross motor deficits, anxiogenic behaviour or gastric ulcers). Conclusions and ImplicationsThese findings suggest that local inhibition of DGL at the site of inflammation represents a novel avenue to treat pathological pain, with no apparent untoward side effects.United States Department of Health & Human Services - DA009789 - DA017259 - DA032933 - DA033934-01A1 DA035864 - DA038493-01A1National Institutes of Health (NIH) - USANIH-NINDS Center core grant - 5P30NS047463United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA - P30NS047463NIH National Institute of Neurological Disorders & Stroke (NINDS)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA - R01DA032933 - K99DA035864 - P01DA017259 - P01DA009789 - F32DA038493 - R00DA035864 - P30DA033934NIH National Institute on Drug Abuse (NIDA)European Commissio

Management of Myelodysplastic Syndrome Relapsing after Allogeneic Hematopoietic Stem Cell Transplantation: A Study by the French Society of Bone Marrow Transplantation and Cell Therapies

To find out prognostic factors and to investigate different therapeutic approaches, we report on 147 consecutive patients who relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndrome (MDS). Sixty-two patients underwent immunotherapy (IT group, second allo-HSCT or donor lymphocyte infusion), 39 received cytoreductive treatment alone (CRT group) and 46 were managed with palliative/supportive cares (PSC group). Two-year rates of overall survival (OS) were 32%, 6%, and 2% in the IT, CRT, and PSC groups, respectively (P < .001). In multivariate analysis, 4 factors adversely influenced 2-year rates of OS: history of acute graft-versus-host disease (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.26 to 2.67; P ¼ .002), relapse within 6 months (HR, 2.69; 95% CI, .82 to 3.98; P < .001), progression to acute myeloid leukemia (HR, 2.59; 95% CI, 1.75 to 3.83; P < .001), and platelet count < 50 G/L at relapse (HR, 1.68; 95% CI, 1.15 to 2.44; P ¼.007). A prognostic score based on those factors discriminated 2 risk groups with median OSs of 13.2 versus 2.4 months, respectively (P < .001). When propensity score, prognostic score, and treatment strategy were included in Cox model, immunotherapy was found to be an independent factor that favorably impacts OS (HR, .40; 95% CI, .26 to .63; P < .001). In conclusion, immunotherapy should be considered when possible for MDS patients relapsing after allo-HSCT

Angioimmunoblastic T-cell lymphoma is the most common T-cell lymphoma in two distinct French information data sets.

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