GENERALIZED CYTOMEGALIC INCLUSION DISEASE

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Neutrosophic Vague Binary G-subalgebra of G-algebra

Nowadays, human society is using artificial intelligence in a large manner so as to upgrade the present existing applicational criteria’s and tools. Logic is the underlying principle to these works. Algebra is inevitably inter-connected with logic. Hence its achievements to the scientific research outputs have to be addressed. For these reasons, nowadays, research on various algebraic structures are going on wide. Crisp set has also got developed in a parallel way in the forms as fuzzy, intuitionistic fuzzy, rough, vague, neutrosophic, plithogenic etc. Sets with one or more algebraic operations will form different new algebraic structures for giving assistance to these logics, which in turn acts to as, a support to artificial intelligence. BCH/BCI/BCK- are some algebras developed in the first phase of algebraic development output. After that, so many outputs got flashed out, individually and in combinations in no time. Q- algebra and QS –algebra are some of these and could be showed as such kind of productions. G- algebra is considered as an extension to QS – algebra. In this paper neutrosophic vague binary G – subalgebra of G – algebra is generated with example. Notions like, 0 – commutative G - subalgebra, minimal element, normal subset etc. are investigated. Conditions to define derivation and regular derivation for this novel concept are clearly presented with example. Constant of G – algebra can’t be treated as the identity element, generally. In this paper, it is well explained with example. Cosets for neutrosophic vague binary G – subalgebra of G - algebra is developed with proper explanation. Homomorphism for this new concept has been also got commented. Its kernel, monomorphism and isomorphism are also have discussed with proper attention

Critical slowing down in momentary affect as early warning signal of impending transitions in depression

Based on dynamical systems theory, the current study aimed to investigate if recurrence of depression is systematically preceded by within-person early warning signals (EWS) in positive and negative affect. Ecological momentary assessments were collected 5 times a day for a period of 4 months (averaging 524 assessments per individual) in 37 formerly depressed individuals discontinuing antidepressant medication. EWS (increases in window autocorrelation and variance) preceded recurrence of depression in 32.9% of the participants across robustness checks. Compared to participants that remained in remission, participants with a recurrence showed (1) significantly more positive trends in the variance, but not in autocorrelation, and (2) the average number of significant EWS was over three times larger across tested affect variables. Although the results provide the first systematic evidence that EWS occur more often before the recurrence of depression, the low sensitivity of EWS poses a substantial challenge for clinical applications

Collaborative model for diagnosis and treatment of very rare diseases: experience in Spain with thymidine kinase 2 deficiency

Malaltia mitocondrial; Medicina mitocondrial; Deficiència de timidina cinasa 2 (TK2d)Mitochondrial disease; Mitochondrial medicine; Thymidine kinase 2 deficiency (TK2d)Enfermedad mitocondrial; Medicina mitocondrial; Deficiencia de timidina cinasa 2 (TK2d)Background Mitochondrial diseases are difficult to diagnose and treat. Recent advances in genetic diagnostics and more effective treatment options can improve patient diagnosis and prognosis, but patients with mitochondrial disease typically experience delays in diagnosis and treatment. Here, we describe a unique collaborative practice model among physicians and scientists in Spain focused on identifying TK2 deficiency (TK2d), an ultra-rare mitochondrial DNA depletion and deletions syndrome. Main Body This collaboration spans research and clinical care, including laboratory scientists, adult and pediatric neuromuscular clinicians, geneticists, and pathologists, and has resulted in diagnosis and consolidation of care for patients with TK2d. The incidence of TK2d is not known; however, the first clinical cases of TK2d were reported in 2001, and only ~ 107 unique cases had been reported as of 2018. This unique collaboration in Spain has led to the diagnosis of more than 30 patients with genetically confirmed TK2d across different regions of the country. Research affiliate centers have led investigative treatment with nucleosides based on understanding of TK2d clinical manifestations and disease mechanisms, which resulted in successful treatment of a TK2d mouse model with nucleotide therapy in 2010. Only 1 year later, this collaboration enabled rapid adoption of treatment with pyrimidine nucleotides (and later, nucleosides) under compassionate use. Success in TK2d diagnosis and treatment in Spain is attributable to two important factors: Spain’s fully public national healthcare system, and the designation in 2015 of major National Reference Centers for Neuromuscular Disorders (CSURs). CSUR networking and dissemination facilitated development of a collaborative care network for TK2d disease, wherein participants share information and protocols to request approval from the Ministry of Health to initiate nucleoside therapy. Data have recently been collected in a retrospective study conducted under a Good Clinical Practice–compliant protocol to support development of a new therapeutic approach for TK2d, a progressive disease with no approved therapies. Conclusions The Spanish experience in diagnosis and treatment of TK2d is a model for the diagnosis and development of new treatments for very rare diseases within an existing healthcare system.This study was sponsored by Zogenix, Inc., and ERN EURO-NMD. The sponsors reviewed the drafts and provided medical writing support for draft preparation

Acció dels andrògens en el testicle: un paper per a la meiosi

La funció que duen a terme els andrògens en l'espermatogènesi és, encara en certa mesura, enigmàtica: mentre que llur implicació és absolutament vital en la iniciació i en el manteniment del procés espermatogènic normal, la seva funció específica encara no està definida de manera precisa. Els andrògens, com les altres hormones esteroïdals, actuen a través del seu corresponent receptor anomenat receptor d'andrògens (AR). Fins avui, no hi ha gaire evidència que recolzi l'existència de diverses isoformes de l'AR com en el cas del sistema estrògensreceptor d'estrògens. Per tant, la pregunta de com els andrògens duen a terme la seva acció en l'espermatogènesi s'ha d'abordar definint dos processos: en primer lloc, s'han d'identifi- car amb total certesa els tipus cell. ulars testiculars capaços de respondre directament a l'estimulació androgènica. De manera específica, la qüestió per resoldre és quins són els tipus cellulars que expressen l'AR en el testicle. En segon lloc, sabent també que el complex del lligand unit a l'AR actua com a factor de transcripció, caldrà determinar quins són els gens que estaran activats o reprimits en les cèll. ules que tenen AR en resposta a l'estimulació androgènica. Fins que aquestes dues preguntes no estiguin contestades amb tota certesa, el mecanisme pel qual els andrògens regulen l'espermatogènesi serà, en el millor dels casos, especulatiu. En aquesta revisió presentem evidència que els andrògens actuen únicament a les cèll. ules somàtiques del testicle, com són les cèll. ules de Sertoli, les de Leydig, les mioides peritubulars i les cèll. ules del múscul llis que envolten els vasos sanguinis. A més a més, també discutim la possibilitat que els andrògens siguin indispensables per a l'inici de la meiosi, encara que continua essent desconegut el mecanisme pel qual els andrògens actuen en aquest procés.The role that androgens play in spermatogenesis still remains enigmatic: whereas their involvement is absolutely vital to the initiation and maintenance of the normal spermatogenic process, their specific role is yet to be defined. Androgens, like other steroid hormones, act via their corresponding receptor termed the androgen receptor (AR). To date, there is little evidence to support the notion that there are multiple forms of AR as is the case for the estrogen-estrogen receptor system. Thus, the question of how androgens manifest their action on spermatogenesis becomes one of defining two processes: First, the cell types within the testis that are capable of responding directly to androgen stimulation must be identified with absolute certainty. Specifically, this question can be stated as what cell types in the testis express AR. Second, given that the ligand-bound AR serves as a transcription factor, the question then becomes what are the genes turned on or off in AR positive cells in response to androgen stimulation? Until these two questions are unequivocally answered, the mechanism of how androgens regulate spermatogenesis will remain speculative at best. In this review we present evidence that androgens act solely at the level of the somatic cells of the testis, including Sertoli cells, Leydig cells, peritubular myoid cells and smooth muscle cells surrounding blood vessels. In addition, we discuss the likely possibility that androgens are indispensable for the onset of meiosis, albeit how they accomplish this remains a mystery

Constitutive and Ghrelin-Dependent GHSR1a activation impairs CaV2.1 and CaV2.2 currents in hypothalamic neurons

The growth hormone secretagogue receptor type 1a (GHSR1a) has the highest known constitutive activity of any G Protein-Coupled receptor (GPCR). GHSR1a mediates the action of the hormone ghrelin, and its activation increases transcriptional and electrical activity in hypothalamic neurons. Although GHSR1a is present at GABAergic presynaptic terminals, its effect on neurotransmitter release remains unclear. The activities of the Voltage-Gated calcium channels, CaV2.1 and CaV2.2, which mediate neurotransmitter release at presynaptic terminals, are modulated by many GPCRs. Here, we show that both constitutive and Agonist-Dependent GHSR1a activity elicit a strong impairment of CaV2.1 and CaV2.2 currents in rat and mouse hypothalamic neurons and in a heterologous expression system. Constitutive GHSR1a activity reduces CaV2 currents by a Gi/o-Dependent mechanism that involves persistent reduction in channel density at the plasma membrane, whereas Ghrelin-Dependent GHSR1a inhibition is reversible and involves altered CaV2 gating via a Gq-Dependent pathway. Thus, GHSR1a differentially inhibits CaV2 channels by Gi/o or Gq protein pathways depending on its mode of activation. Moreover, we present evidence suggesting that GHSR1a-Mediated inhibition of CaV2 attenuates GABA release in hypothalamic neurons, a mechanism that could contribute to neuronal activation through the disinhibition of postsynaptic neurons.Instituto Multidisciplinario de Biología Celula

Constitutive and Ghrelin-Dependent GHSR1a activation impairs CaV2.1 and CaV2.2 currents in hypothalamic neurons

The growth hormone secretagogue receptor type 1a (GHSR1a) has the highest known constitutive activity of any G Protein-Coupled receptor (GPCR). GHSR1a mediates the action of the hormone ghrelin, and its activation increases transcriptional and electrical activity in hypothalamic neurons. Although GHSR1a is present at GABAergic presynaptic terminals, its effect on neurotransmitter release remains unclear. The activities of the Voltage-Gated calcium channels, CaV2.1 and CaV2.2, which mediate neurotransmitter release at presynaptic terminals, are modulated by many GPCRs. Here, we show that both constitutive and Agonist-Dependent GHSR1a activity elicit a strong impairment of CaV2.1 and CaV2.2 currents in rat and mouse hypothalamic neurons and in a heterologous expression system. Constitutive GHSR1a activity reduces CaV2 currents by a Gi/o-Dependent mechanism that involves persistent reduction in channel density at the plasma membrane, whereas Ghrelin-Dependent GHSR1a inhibition is reversible and involves altered CaV2 gating via a Gq-Dependent pathway. Thus, GHSR1a differentially inhibits CaV2 channels by Gi/o or Gq protein pathways depending on its mode of activation. Moreover, we present evidence suggesting that GHSR1a-Mediated inhibition of CaV2 attenuates GABA release in hypothalamic neurons, a mechanism that could contribute to neuronal activation through the disinhibition of postsynaptic neurons.Instituto Multidisciplinario de Biología Celula

Collaborative model for diagnosis and treatment of very rare diseases: experience in Spain with thymidine kinase 2 deficiency

[EN]Background: Mitochondrial diseases are difficult to diagnose and treat. Recent advances in genetic diagnostics and more effective treatment options can improve patient diagnosis and prognosis, but patients with mitochondrial disease typically experience delays in diagnosis and treatment. Here, we describe a unique collaborative practice model among physicians and scientists in Spain focused on identifying TK2 deficiency (TK2d), an ultra-rare mitochondrial DNA depletion and deletions syndrome. Main Body: This collaboration spans research and clinical care, including laboratory scientists, adult and pediatric neuromuscular clinicians, geneticists, and pathologists, and has resulted in diagnosis and consolidation of care for patients with TK2d. The incidence ofTK2d is not known; however, the first clinical cases ofTK2d were reported in 2001, and only similar to 107 unique cases had been reported as of 2018. This unique collaboration in Spain has led to the diagnosis of more than 30 patients with genetically confirmed TK2d across different regions of the country. Research affiliate centers have led investigative treatment with nucleosides based on understanding ofTK2d clinical manifestations and disease mechanisms, which resulted in successful treatment of a TK2d mouse model with nucleotide therapy in 2010. Only 1 year later, this collaboration enabled rapid adoption of treatment with pyrimidine nucleotides (and later, nucleosides) under compassionate use. Success in TK2d diagnosis and treatment in Spain is attributable to two important factors: Spain's fully public national healthcare system, and the designation in 2015 of major National Reference Centers for Neuromuscular Disorders (CSURs). CSUR networking and dissemination facilitated development of a collaborative care network for TK2d disease, wherein participants share information and protocols to request approval from the Ministry of Health to initiate nucleoside therapy. Data have recently been collected in a retrospective study conducted under a Good Clinical Practice-compliant protocol to support development of a new therapeutic approach for TK2d, a progressive disease with no approved therapies. Conclusions: The Spanish experience in diagnosis and treatment of TK2d is a model for the diagnosis and development of new treatments for very rare diseases within an existing healthcare system.This study was sponsored by Zogenix, Inc., and ERN EURO-NMD. The sponsors reviewed the drafts and provided medical writing support for draft preparation

20 anys de Catalunya a la Unió Europea

Aquest llibre aprofita la efemèride del vintè aniversari de la integració de Catalunya a la UE per analitzar l'impacte de les principals polítiques europees i la seva influència en l'evolució de les polítiques a nivell catalàEste libro aprovecha la efeméride del vigésimo aniversario de la integración de Cataluña en la UE para analizar el impacto de las principales políticas europeas y su influencia en la evolución de las políticas a nivel catalá

␥-Hydroxybutyrate (GHB) in Humans Pharmacodynamics and Pharmacokinetics

ABSTRACT: Despite ␥-hydroxybutyrate (GHB) therapeutic uses and the increasing concern about its toxicity, few studies have addressed GHB dose-related effects under controlled administration and their relationship with its pharmacokinetics. The study design was double-blind, randomized, crossover, and controlled. As a pilot pharmacology phase I study, increasing doses of GHB were given. Single oral sodium GHB doses (40, 50, 60, and 72 mg/kg) were administered to eight volunteers. Plasma and urine were analyzed for GHB by gas chromatographymass spectrometry. Physiological effects, psychomotor performance, and subjective effects were examined simultaneously. GHB produced doserelated changes in subjective effects as measured by questionnaires and VAS. GHB showed a mixed stimulant-sedative pattern, with initially increased scores in subjective feeling of euphoria, high, and liking followed by mild-moderate symptoms of sedation with impairment of performance and balance. Mean peak GHB plasma concentrations were 79.1, 83.1, 113.5, and 130.1 g/L for 40, 50, 60, and 72 mg/kg, respectively. GHB-mediated physiological and subjective effects were dose dependent and related to GHB plasma concentrations. GHB urinary excretion was mainly related to administered doses. GHB-mediate