What Are the Arguments For and Against Rational Therapy for Epilepsy?

2014 ◽  
pp. 295-308 ◽  
Author(s):  
Melissa Barker-Haliski ◽  
Graeme J. Sills ◽  
H. Steve White
Keyword(s):  
Rational Therapy

scholarly journals RhoA/ROCK pathway is the major molecular determinant of basal tone in intact human internal anal sphincter

2012 ◽  
Vol 302 (7) ◽  
pp. G664-G675 ◽  
Author(s):  
Satish Rattan ◽  
Jagmohan Singh
Keyword(s):  
Anal Sphincter ◽  
Internal Anal Sphincter ◽  
Control Mechanisms ◽  
Rock Inhibitor ◽  
Critical Determinant ◽  
Molecular Control ◽  
Motility Disorders ◽  
Basal Tone ◽  
Before And After ◽  
Rational Therapy

The knowledge of molecular control mechanisms underlying the basal tone in the intact human internal anal sphincter (IAS) is critical for the pathophysiology and rational therapy for a number of debilitating rectoanal motility disorders. We determined the role of RhoA/ROCK and PKC pathways by comparing the effects of ROCK- and PKC-selective inhibitors Y 27632 and Gö 6850 (10−8to 10−4M), respectively, on the basal tone in the IAS vs. the rectal smooth muscle (RSM). Western blot studies were performed to determine the levels of RhoA/ROCK II, PKC-α, MYPT1, CPI-17, and MLC20in the unphosphorylated and phosphorylated forms, in the IAS vs. RSM. Confocal microscopic studies validated the membrane distribution of ROCK II. Finally, to confirm a direct relationship, we examined the enzymatic activities and changes in the basal IAS tone and p-MYPT1, p-CPI-17, and p-MLC20, before and after Y 27632 and Gö 6850. Data show higher levels of RhoA/ROCK II and related downstream signal transduction proteins in the IAS vs. RSM. In addition, data show a significant correlation between the active RhoA/ROCK levels, ROCK enzymatic activity, downstream proteins, and basal IAS tone, before and after ROCK inhibitor. From these data we conclude 1) RhoA/ROCK and downstream signaling are constitutively active in the IAS, and this pathway (in contrast with PKC) is the critical determinant of the basal tone in intact human IAS; and 2) RhoA and ROCK are potential therapeutic targets for a number of rectoanal motility disorders for which currently there is no satisfactory treatment.

scholarly journals Therapeutic Potential of αS Evolvability for Neuropathic Gaucher Disease

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 289 ◽  
Author(s):  
Jianshe Wei ◽  
Yoshiki Takamatsu ◽  
Ryoko Wada ◽  
Masayo Fujita ◽  
Gilbert Ho ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Lysosomal Storage ◽  
Adult Type ◽  
Recessive Mutations ◽  
Lysosomal Dysfunction ◽  
Increased Risk ◽  
Rational Therapy ◽  
Novel Therapeutic Strategies

Gaucher disease (GD), the most common lysosomal storage disorder (LSD), is caused by autosomal recessive mutations of the glucocerebrosidase gene, GBA1. In the majority of cases, GD has a non-neuropathic chronic form with adult onset (GD1), while other cases are more acute and severer neuropathic forms with early onset (GD2/3). Currently, no radical therapies are established for GD2/3. Notably, GD1, but not GD2/3, is associated with increased risk of Parkinson’s disease (PD), the elucidation of which might provide a clue for novel therapeutic strategies. In this context, the objective of the present study is to discuss that the evolvability of α-synuclein (αS) might be differentially involved in GD subtypes. Hypothetically, aging-associated PD features with accumulation of αS, and the autophagy-lysosomal dysfunction might be an antagonistic pleiotropy phenomenon derived from αS evolvability in the development in GD1, without which neuropathies like GD2/3 might be manifested due to the autophagy-lysosomal dysfunction. Supposing that the increased severity of GD2/3 might be attributed to the decreased activity of αS evolvability, suppressing the expression of β-synuclein (βS), a potential buffer against αS evolvability, might be therapeutically efficient. Of interest, a similar view might be applicable to Niemann-Pick type C (NPC), another LSD, given that the adult type of NPC, which is comorbid with Alzheimer’s disease, exhibits milder medical symptoms compared with those of infantile NPC. Thus, it is predicted that the evolvability of amyloid β and tau, might be beneficial for the adult type of NPC. Collectively, a better understanding of amyloidogenic evolvability in the pathogenesis of LSD may inform rational therapy development.

The use of Octin in peptic ulcer disease

1934 ◽  
Vol 30 (2) ◽  
pp. 307-309
Author(s):  
M. I. Shevlyagina
Keyword(s):  
Peptic Ulcer ◽  
Conservative Treatment ◽  
Peptic Ulcer Disease ◽  
Ulcer Disease ◽  
Rational Therapy

Conservative treatment of peptic ulcer currently is still largely symptomatic and imperfect. It is hardly possible to solve the question of rational therapy until the necessary clarity in the question of ulcer pathogenesis is brought.

IRRATIONAL USE OF MEDICINES IN MEDICAL ORGANIZATIONS OF THE VOLGA FEDERAL DISTRICT. (ON THE EXAMPLE OF THE PENZA REGIONAL CLINICAL HOSPITAL NAMED AFTER N. N. BURDENKO, WHEN PROVIDING SPECIALIZED CARE TO CHILDREN IN THE CONDITIONS OF THE ADULT DEPARTMENT OF ORAL AND MAXILLOFACIAL SURGERY)

2021 ◽  
pp. 168-175
Author(s):  
Lebedev M.V. ◽  
Abdullina Y.A. ◽  
Zakharova I.Y.
Keyword(s):  
Medical Care ◽  
Maxillofacial Surgery ◽  
Federal District ◽  
Oral And Maxillofacial Surgery ◽  
Medical Organization ◽  
Maxillofacial Region ◽  
Clinical Hospital ◽  
Specialized Care ◽  
Rational Therapy ◽  
Medical Histories

The issues of financing in a medical organization are one of the most relevant areas of healthcare in the Russian Federation. Providing departments with the necessary financial resources to provide effective and accessible medical care to the population is important for both the administration and doctors and nurses. In some regions of the Volga Federal District, the departments are combined (Penza, Saransk), that is, all types of medical care are provided to both adults and children in one place, which leads to a number of problems associated with the irrational use of medicines. One of these is the department of Maxillofacial Surgery of the N.N. Burdenko National Clinical Hospital, on the basis of which the disadvantages of using drugs for parenteral use are considered. The purpose of this work is an economic analysis of the effectiveness of the use of solutions for parenteral use in children on the basis of an adult medical organization. The materials of the study were data from patients ' medical histories, prescribing lists, invoices from the pharmacy organization, and data on the cost of medicines. The results of the work are an analysis of the existing problems of combined type departments related to drug provision, a number of medicines for parenteral use that are not available to order, but are included in the standards of treatment of children with injuries of the maxillofacial region. The ABC - analysis of expenses under the item "medicines" is calculated, the data of the VEN – analysis is presented, which includes vital, necessary and secondary medicines for the treatment of children with injuries of the maxillofacial region. An algorithm for the selection of effective and rational therapy has been developed, using the example of antibacterial agents for parenteral administration.

S3-02-04 Neuroserpin provides a structural model for the causation and rational therapy of dementia

2004 ◽  
Vol 25 ◽  
pp. S47-S48
Author(s):  
Robin W. Carrell ◽  
Aiwu Zhou ◽  
David A. Lomas
Keyword(s):  
Structural Model ◽  
Rational Therapy

scholarly journals ETMM-08 METABOLIC REGULATION OF THE EPIGENOME DRIVES LETHAL INFANTILE EPENDYMOMA

2021 ◽  
Vol 3 (Supplement_1) ◽  
pp. i15-i16
Author(s):  
Sachin Kumar ◽  
Antony Michealraj ◽  
Leo Kim ◽  
Jeremy Rich ◽  
Michael Taylor
Keyword(s):  
Metabolic Regulation ◽  
Primary Cultures ◽  
First Trimester ◽  
Transcriptional Analysis ◽  
Cell Of Origin ◽  
H3k27 Trimethylation ◽  
A Genome ◽  
Rational Therapy

Abstract Ependymomas are malignant glial tumours that occur throughout the central nervous system. Of the nine distinct molecular subgroups of ependymoma, Posterior Fossa A (PFA), is the most prevalent, occurring in the hindbrain of infants and young children. Lacking highly recurrent somatic mutations, PFAs are thought to be a largely epigenetically driven entity, defined by hypomethylation at the histone 3 lysine 27 residue. Previous transcriptional analysis of PFAs revealed an enrichment of hypoxia signaling genes. Thus, we hypothesized that hypoxic signaling, in combination with a unique metabolic milieu, drive PFA oncogenesis through epigenetic regulation. In this study, we identified that PFA cells control the availability of specific metabolites under hypoxic conditions, resulting in diminished H3K27 trimethylation and increased H3K27 acetylation in vitro and in vivo. Unique to PFA cells, transient exposure to ambient oxygen results in irreversible cellular toxicity. Furthermore, perturbation of key metabolic pathways is sufficient to inhibit growth of PFA primary cultures in vitro. PFA cells sequester s-adenosylmethionine while upregulating EZHIP, a polycomb repressive complex 2 (PRC2) inhibitor, resulting in decreased H3K27 trimethylation. Furthermore, hypoxia fine-tunes the abundance of alpha-ketoglutarate and acetyl-CoA to fuel demethylase and acetyltransferase activity. Paradoxically, a genome-wide CRISPR knockout screen identified the core components of PRC2 as uniquely essential in PFAs. Our findings suggest that PFAs thrive in a narrow “Goldilocks” zone, whereby they must maintain a unique epigenome and deviation to increased or decreased H3K27 trimethylation results in diminished cellular fitness. Previously, we showed that PFAs have a putative cell of origin arising in the first trimester of development. Using single-cell RNAseq and metabolomics, we demonstrate that PFAs resemble the natural metabolic-hypoxic milieu of normal development. Therefore, targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.

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